Methods and compositions for treating cancer using n-myristoyltransferase inhibitors

Abstract

Methods of treating a subject for cancer are provided. Aspects of the methods include administering to the subject a N-myristoyltransferase inhibitor, optionally in combination with a proteasome inhibitor and / or chemotherapeutic agent, to treat the subject for cancer. Also provided are compositions, e.g., that comprise synergistically effective amounts of a N-myristoyltransferase inhibitor and a proteasome inhibitor and / or a chemotherapeutic agent.

Description

[0001] Atty. Docket No.: LABIO-006WO METHODS AND COMPOSITIONS FOR TREATING CANCER USING N-MYRISTOYLTRANSFERASE INHIBITORS CROSS-REFERENCEThis application claims the benefit of U.S. Provisional Patent Application No.63 / 687,007 filed August 26, 2024, which application is incorporated herein by reference in its entirety. INTRODUCTION Cancer is a large group of diseases that can start in almost any organ or tissue of the body when abnormal cells grow uncontrollably, go beyond their usual boundaries to invade adjoining parts of the body and / or spread to other organs. The latter process is called metastasizing and is a major cause of death from cancer. A neoplasm and malignant tumor are other common names for cancer. Cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths, or one in six deaths, in 2018. Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical and thyroid cancer are the most common among women. The cancer burden continues to grow globally, exerting tremendous physical, emotional and financial strain on individuals, families, communities and health systems. Many health systems in low- and middle-income countries are least prepared to manage this burden, and large numbers of cancer patients globally do not have access to timely quality diagnosis and treatment. In countries where health systems are strong, survival rates of many types of cancers are improving thanks to accessible early detection, quality treatment and survivorship care. (www.who.int / health-topics / cancer#tab=tab_1). SUMMARYMethods of treating a subject for provided. Aspects of the methods include administering to the subject a N-myristoyltransferase inhibitor, optionally in combination with a proteasome inhibitor and / or a chemotherapeutic agent, to treat the subject for cancer. Also provided are compositions, e.g., that comprise synergistically effective amounts of a N- myristoyltransferase inhibitor (NMTi) and a proteasome inhibitor and / or a chemotherapeutic agent. In some embodiments (methods and / or compositions), the NMTi includes at least one of: DDD86481 (PCLX-001), DDD85646 (IMP-366; PCLX-002), and IMP-1088. For example, in Atty. Docket No.: LABIO-006WO some cases, the NMTi includes DDD86481 (also known as “PCLX-001”). In some cases, PCLX- 001 is co-administered with a proteasome inhibitor such as bortezomib. For example, in some cases, a subject pharmaceutical composition includes a synergistically effective amount of an NMTi (such as PCLX-001) and a proteasome inhibitor (such as bortezomib). In some embodiments, a subject method is a method of killing an apoptosis-resistant lung carcinoma cell, where the cell is contacted with an NMTi such as DD85646, DDD86481, or IMP-1088. In some cases, the NMTi includes DDD86481. In some embodiments, a subject method is a method of treating a subject for therapy resistant lung cancer, where an NMTi such as DD85646, DDD86481, or IMP-1088 is administered to the subject. In some such cases, the NMTi includes DDD86481. In some embodiments, the apoptosis-resistant lung carcinoma cell includes a KRAS / LKB / KEAP1 mutational signature (e.g., (i) KRAS mutation plus LKB1 mutation; or (ii) KRAS mutation plus KEAP1 mutation; or (iii) KRAS mutation plus LKB1 mutation plus KEAP1 mutation). For example, in some embodiments, a subject who is being treated has a therapy-resistant lung cancer characterized by the presence of apoptosis-resistant lung cancer cells that have a KRAS / LKB / KEAP1 mutational signature. In some embodiments (methods and / or compositions), a subject method is a method of treating a subject for cancer (e.g., a lung cancer such as NSCLC), where the method includes administering an NMTi (such as DDD85646, DDD86481, or IMP-1088) and a chemotherapeutic agent (such as a DNA damaging chemotherapeutic agent) to the subject. In some cases, the NMTi includes PCLX-001 and the chemotherapeutic agent includes pemetrexed and a platinum- based compound (e.g., cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, lobaplatin). In some such cases, the chemotherapeutic agent includes pemetrexed and cisplatin. In some embodiments (methods and / or compositions), a subject method is a method of killing lung cancer cell (e.g., a lung cancer cells such as an NSCLC cell), where the method includes contacting the lunger cancer cell with an NMTi (such as DDD85646, DDD86481, or IMP-1088), wherein the lung cancer cell is TIM17A dependent. In some cases, the NMTi includes PCLX-001. Likewise, in some embodiments (methods and / or compositions), a subject method is a method of treating a subject for lung cancer (e.g., a lung cancer such as NSCLC), where the method includes administering an NMTi (such as DDD85646, DDD86481, or IMP- 1088), wherein the lung cancer is TIM17A dependent. In some cases, the NMTi includes PCLX-001. In some cases, a subject method includes determining that the lung cancer (or lung cancer cell) exhibits increased TIM17A dependence relative to a control, prior to the contacting, or prior to the administering. Atty. Docket No.: LABIO-006WO BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. FIG.1A-1B Synergistic effect of DDD85646 and bortezomib against lung carcinoma cells in vitro. (A) Viability assay (CCK8, Dojindo) of H460 cells treated with the indicated concentrations of bortezomib for 48 hours. EC20 was calculated as 30 nanomolar. (B) Viability assay (CCK8, Dojindo) of H460 cells treated with the indicated micromolar concentrations of DDD85646 alone or in combination with bortezomib (EC20, 30 nanomolar). FIG.2A-2E Lung carcinoma cells with LKB1 and / or KEAP1 mutations in a KRAS mutant background are sensitive to myristoylation inhibition. (A) NMTi IC50 for lung carcinoma cells with the indicated mutational status were compared. IC50 values for ICL1100013 (DDD85646) were from Genomics of drug sensitivity in Cancer and mutational profiles from DepMap. (**) P=0.008, (*) P=0.005, ns=not significant (Student’s t-test). Crossbar, median. (B) Viability test (CCK8) at 72 hours of PCLX-001 treatment. Optical density (OD) values were normalized to vehicle-treated samples. Error bars, SEM. (C) NMT1 immunoblotting on the indicated cells. GAPDH, loading control. (D) Relative viability (CCK8) of doxycycline (dox) treated vs. untreated Tet-inducible NMT1#10 shRNA cells. Blot: NMT1 immunoblotting in cells with or without Dox. GAPDH, loading control. (E) Percent change in H460 (KL / K)MUTxenograft tumor volume from mice treated with daily subcutaneous injections of vehicle control or PCLX- 001 at dosages of 25 and 50 mg / kg. Treatment was indicated by the colored bars (18 days for the 25 mg / kg group and 10 days for the 50 mg / kg group). (**) P=0.008, one-way Anova, Tukey's multiple comparisons test. FIG.3A-3D NMT inhibition causes mitochondrial ferrous iron accumulation and increases ROS in (KL / K)MUTbut not (KL / K)WTlung carcinoma cells. (A) TfR1 and DAPI staining on (KL / K)MUTH460 cells treated with 0.5 μM DDD85646 (NMTi) or vehicle for 72 hours. Images were inverted for clarity. Right column, amplification of the area in the square in the middle column. Bar, 15 μm in left and middle columns, 5 μm in right column. (*), endocytic recycling compartment. Arrowheads, intracellular TfR1 clusters. (B) Cytoplasmic ferrous iron measured using FerroOrange in H460 cells (KL / K)MUTtreated with 0.5 μM DDD85646 (NMTi) or vehicle for the indicated times. Two independent experiments with four technical replicates each were combined. Deferoxamine (DFO, 7 μM) was used as negative control. Fluorescence was normalized to cell number and expressed as arbitrary units (a.u.). Bar, group mean; error bars, Atty. Docket No.: LABIO-006WO SD. (**) p=0.0014, (***) p=0.0002, ns=not significant (Student’s t-test). (C) Mitochondrial ferrous iron (Mito-FerroGreen) measured in (KL / K)MUTand (KL / K)WTlung carcinoma cells treated with 1μM DDD85646 or vehicle for 24 hours. Signal intensity was quantified in randomly imaged fields containing at least 200 cells per condition. Bar, group mean; error bars, SEM; a.u., arbitrary units. (***) p=0.0002, ns=not significant (Student’s t-test). Representative images are shown. Bar,15μm. (D) Reactive oxygen species (ROS) detected using DCFH-DA in (KL / K)MUTand (KL / K)WTlung carcinoma cells treated with 1μM DDD85646 for the indicated times. Signal intensity was quantified in randomly imaged fields containing at least 720 cells per condition. Bars, mean; error bars, SEM; a.u., arbitrary units. (*) p=0.0202, (****) p<0.0001, (**) p=0.0017, ns, not significant (Student’s t-test). Representative images from 72 hours of treatment are shown. Bar, 30 μm. FIG.4A-4C NMT inhibition increases lipid peroxidation and induces caspase- independent cell death in (KL / K)MUTlung carcinoma cells. (A) Lipid peroxidation measured using Bodipy 581 / 591 C11 and flow cytometry in (KL / K)MUTand (KL / K)WTlung carcinoma cells treated with 1 μM DDD85646 (NMTi) or vehicle control (DMSO) for 96 hours. Erastin (10 μM for 24 hours) was used as positive control. Green fluorescence (oxidized probe) was normalized to control DMSO. n=2 independent experiments. MFI, mean fluorescence intensity. (B) Cell viability (Live / dead reagent) was analyzed in (KL / K)MUTcells treated for 72 hours with vehicle control or 1 μM DDD85646 (NMTi) in the presence or absence of 25 μM ZVAD-FMK added freshly every 24 hours. Graph: percentage of dead cells calculated from at least 5,000 cells per condition. Bar, group mean, error bars, SEM. (****) p<0.0001, ns=not significant (Student’s t- test). Representative images are shown. Bar, 100 μm. (C) Cell viability (Live / dead reagent) analyzed in (KL / K)MUTcells treated for 72 hours with vehicle control or 1 μM DDD85646 (NMTi) in the presence or absence of the ferroptosis inhibitor Liproxstatin (5 and 10 μM). Graph: percentage of dead cells calculated from at least 5,500 cells per condition. Crossbar, group mean; error bars, SEM. (*) p<0.05, ns=not significant (Student’s t-test). Representative images are shown. Bar, 100 μm. FIG.5A-5H NMTi treatment induces parthanatos in (KL / K)MUTlung carcinoma cells. (A) Ultrastructure of (KL / K)MUTcells treated with 1 μM DDD85646 (NMTi) or vehicle control for 72 hours. Lower panels, magnification of areas in the squares. Arrowheads, mitochondria. Bars, 1 μm (upper panels) and 0.5 μm (lower panels). (B) Diagram of the parthanatos components. (C) Detection of poly-ADP ribosylation (PAR) by immunoblotting in lysates from (KL / K)MUTcells treated with 1 μM PCLX-001 (NMTi) for 72 hours. Actin, loading control. (D) Detection of poly- ADP ribosylation (PAR) by immunoblotting in lysates from (KL / K)MUTH460 and (KL / K)WTH1437 Atty. Docket No.: LABIO-006WO cells expressing Tet-inducible NMT1 shRNA treated with or without Dox. GAPDH, loading control. Note that GAPDH is identical to that in FIG.2E because the same membrane was used to stain NMT1 and PAR. (E) MIF subcellular localization in (KL / K)MUTH1792 cells treated with vehicle control of 1 μM PCLX-001 (NMTi) for 96 hours and processed for immunofluorescence using a MIF antibody. Representative images are shown. Bar, 5 μm in left column, 15 μm in right column. (F) AIF1 immunoblotting in cytoplasmic and nuclear lysates of (KL / K)MUTH460 treated with 1 μM PCLX-001 (NMTi) o vehicle for 72 hours. Tubulin and Lamin staining were used to verify fraction purity. (*) non-specific band. (G) AIF immunofluorescence in tumor sections from (KL / K)MUTH460 xenografts from animals treated with 25 mg / kg PCLX-001 (NMTi) or vehicle control. Arrowheads, nuclear AIF. Bar, 10 μm. (H) Cell viability (Live / dead reagent) in (KL / K)MUTH460 cells treated with 1 μM PCLX-001 (NMTi) or vehicle control and 20 μM Olaparib for 72 hours. Representative fluorescent images are shown. Bar, 30μm. Graph, percentage of dead cells calculated from at least 5,000 cells per condition. Crossbar, group mean; error bars, SEM. (****) p<0.0001 (Student’s t-test). FIG.6A-6C NMTi treatment activates the DNA damage response and sensitizes (KL / K)MUTlung carcinoma cells to platinum doublet chemotherapy. (A) Phospho-H2A.X staining in (KL / K)MUTH460 lung cancer cells treated with 1 μM PCLX-001 (NMTi) or vehicle control for 72 hours. Graph: percentage of p-H2A.X positive cells calculated from at least 400 cells per condition. Crossbar, group mean; error bars, SEM. (***) p<0.0002 (Student’s t-test). Representative images are shown. Arrowheads, nuclei containing p-H2A.X-positive foci. Bar, 25 μm. (B) Phospho-H2A.X staining of H460 xenograft tumor sections from mice treated with 25 mg / Kg PCLX-001 or vehicle control. Square, area magnified for each panel on the right. Arrowhead, nuclei with p-H2A.X positive foci. Bar, 100, 30 and 10μm in left, middle and right columns respectively. (C) Viability test (CCK8) of (KL / K)MUTHCC44 and H1792 cells treated with PCLX-001 (NMTi) in combination with platinum-based chemotherapy. Left: Dose-response of Cisplatin in combination with NMTi (50 nM). Middle: dose-response of Pemetrexed in combination with NMTi (50 nM). Right: dose-response of Cisplatin in combination with a single dose of Pemetrexed (5 μM) and a single dose of NMTi (125 nM). Optical density (OD) was normalized to vehicle-treated samples. One representative experiment from two independent experiments with the same result is shown. Error bars, SEM. (**) p<0.0001, (*) p<0.0025, two- way ANOVA with the interaction between drug and dose level. All P values are adjusted for multiple testing using the Šídák method. FIG.7A-7F Mitochondria are a key target of NMT inhibition in (KL / K)MUTlung carcinoma cells. (A) Ultrastructure of mitochondria from (KL / K)MUTH1792 lung carcinoma cells Atty. Docket No.: LABIO-006WO treated with control or 1 μM DDD85646 (NMTi) for the indicated times. Arrowheads, mitochondria cristae. Bar, 50 nm. (B) Volcano plot of mitochondrial membrane-associated proteins whose abundance was altered by NMTi treatment. Blue lines indicate thresholds for a fold-change of two or a P-value of 0.05 by moderated t-test. (C) Diagram of the main mitochondrial import complexes: TOM, in the outer mitochondrial membrane (OMM) and TIM23, in the inner mitochondrial membrane (IMM). TIM17A or TIM17B bind TIM23 to form the main TIM23 complex channel in the IMM. (D) Kaplan-Meier curve shows percent surviving (overall survival, y-axis) over time (years, x-axis) for TCGA LUAD (n=501, n-event=181). High TIM17A (Red, ≥50th percentile) were compared to low TIM17A (Blue, <50th percentile) (log-rank test, P=0.014, median OS was 3.72 years in TIM17A High vs.4.93 in TIM17A Low). Colored shading: 95% confidence interval. (E) Immunoblotting for TIM17A and TIM17B in samples from (KL / K)MUTH460 cells treated with 1 μM PCLX-001 (NMTi) or vehicle control for the indicated times. Numbers, band intensity normalized to actin control. (F) Immunoblotting for HSP60 and TOM20 in samples from (KL / K)MUTH460 cells treated with 1 μM PCLX-001 (NMTi) or vehicle control for the indicated times. Numbers, band intensity normalized to actin. FIG.8A-8E Dependency on TIM17A is a determinant of NMTi sensitivity in lung carcinoma cells. (A) TIM17A immunoblotting in the indicated cells treated with 1 μM PCLX-001 (NMTi) for 72 hours. Numbers, band intensity normalized to actin control. (B) Boxplot showing CRISPR DepMap Score for lung adenocarcinoma cells (y-axis) estimated using the Chronos algorithm. Negative values suggest decreased cell viability. (KL / K)MUT(HCC44, H460 and H1792) and (KL / K)WT(H522, H1650 and H1437) lung carcinoma cells used in our study are highlighted. (C) TIM17A Crispr Chronos scores (y-axis) plotted against NMTi IC50 (x-axis) (Spearman’s Correlation, P=0.006, ⍴ = -0.43). Axis scales are log-transformed, and best fit line (blue) was calculated using linear model. Grey shading, standard error of the estimate. H460 was added manually based on our calculated IC50 and the publicly available dependency score. (D) Cell viability (crystal violet staining) in (KL / K)MUTH1792 and (KL / K)WTH522 lung carcinoma cells transfected with a TIM17-targeting siRNA pool or a non-targeting control. Bar: average; error bars, SEM. One representative experiment from three independent experiments with similar results. (***) p=0.0009 (Student’s t-test). Bottom: TIM17A immunoblotting of the samples above. (E) Colony assays of (KL / K)MUTH460 and (KL / K)WTH522 expressing Tet-inducible TIM17A or control non targeting shRNA growing in the presence or absence of Doxycycline (Dox). Top: representative images. Bottom, TIM17A immunoblotting of lysates from the cells used for colony assays. GAPDH, loading control. Atty. Docket No.: LABIO-006WO FIG.9A-9E Genetic targeting of TIM17A causes mitochondrial ferrous iron accumulation and activation of parthanatos in (KL / K)MUTlung carcinoma cells. (A) Mitochondrial ferrous iron detection in (KL / K)MUTand (KL / K)WTcells transfected with non- targeting control or two different TIM17A siRNAs. Quantification of signal intensity on a representative experiment out of two using randomly imaged fields containing at least 480 cells per experimental condition. Graph bars, group mean; error bars, SEM. a.u., arbitrary units. (*) p=0.0101 for control vs. #1, p=0.0131 for control vs. #2; ns=not significant (Student’s t-test). Representative microscope images are shown. Arrowheads, Mito-FerroGreen positive cells. Bars, 15 μm. Bottom: TIM17A immunoblotting in lysates from the cells used above. Numbers: band intensity normalized to actin control. (B) Protein PARylation detection by immunoblotting in H1792 cells transfected with non-targeting control and two different TIM17A oligos for 72 hours. Numbers: band intensity normalized to actin control. (C) H460 cells stably expressing a Tet- inducible TIM17A shRNA treated or not with doxycycline (Dox) were stained with p-H2A.X and DAPI. Arrowheads, nuclei containing p-H2A.X-positive foci. Bar, 10 μm. (D) AIF subcellular localization in (KL / K)MUTH460 cells stably expressing a Tet-inducible TIM17A shRNA treated or not with doxycycline (Dox). Cytoplasmic and nuclear lysates were separated and immunoblotted for AIF. Tubulin, TOM20 and Lamin staining were used to verify fraction purity. Numbers: nuclear AIF band intensity normalized to Lamin A / B. (E) Summary of our findings reporting that myristoylation inhibition induces parthanatos through loss of TIM17A and mitochondrial ferrous iron overload in (KL / K)MUTlung carcinoma. FIG.10A-10G NMT1 is a therapeutic target in lung carcinoma. (A) Kaplan-Meier curve showing percent surviving over time for TCGA, Lung Adenocarcinoma (LUAD) dataset (n=501, n-event=181). Survival probability of patients with cancers expressing high NMT1 (Red, ≥80th percentile) and with low NMT1 (Blue, <20th percentile) was different (log-rank test, P=0.0016, median OS was 2.81 years in NMT1 High vs.4.38 in NMT1 Low). Colored shading shows 95% confidence interval. (B) Viability test (cell TiterGlo) of the indicated cell lines treated with NMTi (DDD85646) for 72 hours was used to calculate IC50. (C) Structure of the NMT inhibitors used in this study: DDD85646 (PubChem CID 44199337), PCLX-001 (PubChem CID 58561243) and IMP-1088 (PubChem CID 132274735). (D, E) Viability (CCK8) of the indicated cells treated with the NMT inhibitors IMP-1088 (D) and DDD85646 (E) for 72 hours. Optical density (OD) was normalized to vehicle-treated sample. Error bars, SEM. (F) Viability (CCK8) of Doxycycline (Dox) treated vs. untreated cells stably expressing Tet-inducible non-targeting control shRNA. (G) Colony assay using H460 Tet-inducible cell lines expressing two different shRNA sequences targeting NMT1 (#10 and #68) and a non-targeting shRNA control. Graphs Atty. Docket No.: LABIO-006WO show quantification of percent covered area. (**) p=0.0017, (***) p=0.0004, ns=not significant (Student’s t-test). Right: Representative images of colony assays. Bottom: NMT1 immunoblotting of lysates from H460 Tet-inducible cells expressing NMT1 shRNAs # 68 and #10 treated with Dox for 72 hours in a dose-response manner. Numbers below lanes, band intensity normalized to GAPDH control. FIG.11A-11D Genetic targeting of NMT1 decreases the viability of (KL / K)MUTlung carcinoma. (A) Colony assay of (KL / K)MUTH1792 cells expressing Tet-inducible non-targeting or NMT1 #10 shRNAs in the presence or absence of Doxycycline (Dox). Bottom, graphs showing quantification (percent covered area). (**) p=0.0028, ns=not significant (Student’s t- test). (B) Colony assay using (KL / K)MUTHCC44 cells stably expressing Tet-inducible control or NMT1 #10 shRNAs growth in the presence or absence of Doxycycline (Dox). Representative images from wells are shown. Bottom, graphs showing quantification (percent covered area). (**) p=0.0019, ns=not significant (Student’s t-test). (C) H460 xenograft tumor volume (mm3) from mice treated with vehicle control or PCLX-001 (25 and 50 mg / kg). Control, n=9; 25 mg / kg n=10; 50 mg / kg, n=10. Arrowheads, day of study at which an animal was lost in the 50 mg / kg group (1, 9, 10 and 14). (D) Relative change in body weight of mice treated with vehicle control or PCLX-001 (25 and 50 mg / kg). Length of treatment was indicated by the colored bars (18 days for 25 mg / kg group, and 10 days for 50 mg / kg group). FIG.12A-12E Inhibition of NMT alters iron homeostasis in (KL / K)MUTlung carcinoma cells. (A) Gene Ontology (GO) biological processes significantly over-represented in (KL / K)MUTH1792 treated for 48 hours with 1 μM DDD85646 (NMTi) when compared with DMSO control (Fisher’s Exact Test, P-adjusted < 0.05). Global proteomics data was analyzed. Input for over-representation analysis used 765 / 4,929 uniprot IDs overexpressed with NMTi treatment (P < 0.05). (B) Representative images of TfR1 and DAPI staining in H460 cells treated with vehicle control (DMSO) or 0.5 μM DDD85646 (NMTi) for 72 hours, or with 0.5 μM DDD85646 for 72 hours followed for 24 hours recovery (NMTi washout). TfR1 images were inverted for clarity. Bar, 10 μm in upper panels and 30 μm in lower panels. (C) Effect of iron supplementation (100 μM ferric citrate) on the colony forming ability of H460 cells treated with vehicle control (DMSO) or 0.125 μM DDD85646 (NMTi). Graph: colony number (average and SEM). (**) p=0.0064 (Student’s t-test). (D) Total iron content (ng of iron / million cells) measured using ICP-MS in (KL / K)MUTcells (H460) treated with 0.5 μM DDD85646 (NMTi) for the indicated times. Three independent experiments were combined. Error bars, SD; ns=not significant (Student’s t-test). (E) Cellular ferric iron content detected with enhanced Perls’ Prussian blue staining in (KL / K)MUTlung carcinoma cells (H1792) treated with 0.5 μM DDD85646 (NMTi) for Atty. Docket No.: LABIO-006WO the indicated times. Left: Graph: average and SEM of normalized signal (percent area covered normalized to cell number) from a representative experiment out of two with similar results. (*) p=0.0315 (Student’s t-test). Right: representative images for vehicle (DMSO) and NMTi treated cells at 24 hours after treatment. Arrowheads: ferric iron deposits inside cells. Bars, 60 μm (upper panels) and 15 μm (lower panels). FIG.13A-13D Inhibition of NMT increases mitochondrial ferrous iron content in KL / KMUTbut not KLKWTlung carcinoma cells. (A) Cytoplasmic ferrous iron measured by FerroOrange fluorescence in (KL / K)MUTH1792 cells treated with 0.5 μM DDD85646 (NMTi) or vehicle for the indicated times. Two independent experiments with four technical replicates were combined. Bar, mean; error bars, SD. Deferoxamine (DFO, 7 μM) served as negative control. Fluorescence was normalized to cell number and expressed as arbitrary units (a.u.). ns=not significant. (*) p=0.0112, (****) p <0.0001 (Student’s t-test). for control vs. NMTi (24 hours); df=7 for all. (B) Mitochondrial ferrous iron (Mito-FerroGreen) measured in (KL / K)MUTH460 and (KL / K)WTH1650 cells. Signal intensities were quantified from a representative experiment out of two independent experiments using randomly imaged fields containing at least 150 cells per condition. Barplot bars, group mean; error bars, SEM; a.u., arbitrary units. Left: H460 cells. (**) p=0.0062, ns=not significant (Student’s t-test). Right: H1650 cells. ns=not significant (Student’s t-test). Representative images correspond to 24 hours of treatment. Bar, 20 μm. (C) Mitochondrial ferrous iron (Mito-FerroGreen) in HeLa cells transfected with non-targeting control or NMT1-targeting siRNA pools. Graph: quantification of signal intensity on a representative experiment out of two using randomly imaged fields containing at least 240 cells per condition. Crossbar, group mean. error bars, SEM; a.u., arbitrary units, ns=not significant (Student’s t- test). Representative microscope images of 24 hours treatment are shown. Bar, 20μm. Right: NMT1 immunoblotting in lysates from HeLa cells transfected with NMT1 siRNA. GAPDH, loading control. (D) Reactive oxygen species (ROS) detected using DCFH-DA in (KL / K)MUTH460 and (KL / K)WTH1650 cells treated with 1μM DDD85646 (NMTi) for the indicated times. Signal intensity was quantified in randomly imaged fields containing at least 720 cells per condition. Bar plot bars, group mean; error bars, SEM; a.u., arbitrary units. Left: H460 cells. (*) p=0.0254 (24 hours) (*) p=0.0113, (48 hours); (**) p=0.0071 (Student’s t-test). Right: H1650 cells. (*) p= 0.0265; (**) p= 0.0011, ns=not significant (Student’s t-test). Representative microscope images (72 hours). Bar, 30μm. FIG.14A-14I Inhibition of NMT increases mitochondrial ferrous iron content in (KL / K)MUTbut not (KL / K)WTlung carcinoma cells. (A-B) Lipid peroxidation measured using Bodipy 581 / 591 C11 in (KL / K)MUTH460 cells treated with 1 μM DDD85646 (NMTi) in a time- Atty. Docket No.: LABIO-006WO course (A) and dose-response manner (B). Green fluorescence (oxidized probe) for each treatment was normalized to control DMSO. n=2 independent experiments. MFI, mean fluorescence intensity. (C) Lipid peroxidation measured using Bodipy 581 / 591 C11 in (KL / K)MUTH460 cells treated for 72 hours with vehicle control (DMSO) and the NMT inhibitors DDD85646 (1 μM), IMP-1088 (0.25 μM) and PCLX-001 (0.25 μM). Green fluorescence (oxidized lipid probe) for each treatment was normalized to control DMSO. (D) Lipid peroxidation measured using Bodipy 581 / 591 C11 in (KL / K)MUTH460 cells treated for 48 hours with vehicle control (DMSO) and 1 μM DDD85646 (NMTi) in the presence or absence of the antioxidant Trolox (400 μM) added 24 hours before treatment and replaced along with NMTi treatment. Green fluorescence (oxidized lipid probe) for each treatment was normalized to control DMSO. (E) Lipid peroxidation measured using Bodipy 581 / 591 C11 in (KL / K)MUTH460 cells treated for 48 hours with vehicle control (DMSO) and 1 μM DDD85646 (NMTi) in the presence or absence of 7 μM deferoxamine (DFO). Green fluorescence (oxidized lipid probe) for each treatment was normalized to control DMSO. (F) Lipid peroxidation measured using Bodipy 581 / 591 C11 in HeLa cells treated with vehicle control (DMSO) or DDD85646 (2 μM) for 96 hours. Green fluorescence (oxidized lipid probe) for each treatment was normalized to control DMSO. MFI, mean fluorescence intensity. (G) Lipid peroxidation measured using Bodipy 581 / 591 C11 in HeLa cells transfected with NMT1 siRNA or non-targeting control siRNA. Green fluorescence (oxidized lipid probe) was normalized to control not-targeting oligo. Degree of NMT1 knock- down was shown in FIG.13, C. (H) Immunoblotting for FSP1 on extracts from H460 cells treated with DDD85646 (1 μM) for 72 hours. GAPDH, loading control. (I) Colony assay of H460 cells pre-treated with DMSO control or 5 μM FSP1 inhibitor (iFSP1) for 24 hours before adding DMSO or 0.125 μM DDD85646 (NMTi) in the presence or absence of fresh iFSP1 (5 μM). Cells were stained with crystal violet 10 days after plating and number of colonies quantified using Image J. Graph, average and SEM for a representative experiment from two independent experiments. (**) p=0.0013, (****) p<0.0001 (Student’s t-test). FIG.15A-15C Inhibition of NMT prevents cell cycle progression and causes death in lung carcinoma cells. (A) Cell cycle analysis (Dean Jett-Fox method) using propidium iodide staining and flow cytometry on (KL / K)MUTH1792 cells treated with 1 μM DDD85646 (NMTi) for 24 or 48 hours. Table represents the percentage of cells on each cell cycle phase. N=2. (B) Cell dead (Annexin-V and PI staining) of (KL / K)MUTH460 cells treated with vehicle control (DMSO) or 1 μM DDD85646 (NMTi) for 96 hours analyzed by flow cytometry. Percentage of cells in quadrants 1-3 is shown. (C) Cell viability (Live / dead cell reagent) of H460 cells treated with vehicle control, 0.2 μM Staurosporin (STS, apoptosis inducer) for 24 hours in the presence or Atty. Docket No.: LABIO-006WO absence of the apoptosis inhibitor ZVAD-FMK (25 and 50 μM). Graph: percentage of dead cells calculated from at least 3,500 cells per condition. Crossbar, group mean; error bars, SEM. (****) p<0.0001(Student’s t-test). Representative images are shown on the right panels. Bar, 100 μm. FIG.16A-16C Treatment with necroptosis and pyroptosis inhibitors fail to prevent cell death induced by of NMTi treatment in lung carcinoma cells. (A) Viability test (CCK8) on the indicated cells treated for 72 hours with vehicle control (DMSO) or 125 nM of DDD855646 (NMTi) in the presence or absence of 10 μM Liproxstatin (ferroptosis inhibitor). Graphs: representative experiment from at least two independent experiments. Normalized cell viability was calculated from optical density values from compound-treated samples normalized to vehicle-treated ones. (****) p<0.0001 (Student’s t-test). (B) Cell viability (Live / dead reagent) analyzed in H460 cells treated for 72 hours with vehicle control and 1 μM DDD85646 (NMTi) in the presence or absence of 2.5 μM Disulfiram (pyroptosis inhibitor). Graph: percentage of dead cells calculated from at least 4,300 cells per condition. Crossbar, group mean. error bars, SEM. ns=not significant (Student’s t-test). Representative images are shown in the right panels. (C) Cell viability (Live / dead reagent) was analyzed in H460 cells treated for 72 hours with vehicle control and 1 μM DDD85646 (NMTi) in the absence or presence of 10 and 20 μM Necrostatin-1 (necroptosis inhibitor). Graph: percentage of dead cells calculated from at least 4,500 cells per condition. Crossbar, group mean. error bars, SEM. ns=not significant (Student’s t-test). Representative images are shown in the right panels. FIG.17A-17D NMTi treatment induces features of parthanatos in vitro and in vivo. (A) Nuclei morphology (DAPI staining) of H1792 and HeLa cells treated with 1 μM PCLX-001 (NMTi) for 96 hours. Arrowheads, nuclei with chromatin fragmentation. Bar, 5 μm. (B) MIF antibody staining of H460 cells treated with vehicle control (DMSO) or 1 μM PCLX-001 (NMTi) for 96 hours. Representative images from two independent experiments are shown. Arrowheads, nuclei. Bar, 5 μm in left column and 15 μm in right column. (C) Detection of PARylation by immunoblotting using a PAR antibody in extracts from H460 cells treated with 1 μM PCLX-001 (NMTi) or 1 μM PCLX-001 (NMTi) in combination with 20 μM Olaparib for 96 hours. Actin was used as loading control. (D) AIF subcellular localization analyzed by immunohistochemistry in sections from (KL / K)MUTH460 xenografts from animals treated with 25 mg / kg PCLX-001 (NMTi) or vehicle control. Arrowheads, nuclear AIF. Bar, 100 μm (left column) and 30 μm (right column). Square in left column panels: area magnified in the right column. Square in right column panels: area shown in FIG.5G. FIG.18A-18C The PARP inhibitor Olaparib rescues death induced by NMTi treatment. (A) Cell viability (Live / dead imaging reagent) analyzed in (KL / K)MUTH1792 cells Atty. Docket No.: LABIO-006WO treated with vehicle control or 1 μM PCLX-001 (NMTi) alone or in combination with 5 and 10 μM Olaparib for 72 hours. Graph: percentage of dead cells calculated from at least 4,800 cells per condition. Crossbar, group mean. (*) p=0.0201, (****) p<0.0001 (Student’s t-test). Representative fluorescent images from one out of two independent experiments are shown. Bar, 30 μm. (B) Cell death (propidium iodide staining of live cells) analyzed by flow cytometry in H460 cells treated for 96 hours with vehicle control (DMSO), 1 μM PCLX-001 (NMTi) and 1 μM PCLX-001 in combination with 20 μM Olaparib. Percentages of PI-positive (dead) cells are indicated. (C) Cell viability (Live / dead imaging reagent) was analyzed in (KL / K)MUTH460 cells treated for 96 hours with vehicle control or 1 μM PCLX-001 (NMTi) alone or in combination with 20 μM Olaparib. Graph: percentage of dead cells calculated from at least 4,400 cells per condition Crossbar, group mean. (****) p<0.0001 (Student’s t-test). Representative fluorescent images from one out of two independent experiments are shown. Bar, 30 μm. FIG.19A-19F Mitochondria is a key target of NMT inhibitors. (A) Gene Ontology (GO) biological processes significantly over-represented in proteomics assay of DMSO-treated control group compared DDD85646 (NMTi) treated group for 48 hours (Fisher’s Exact Test, P- adjusted < 0.05; *, qval < 0.001). Input for over-representation analysis used 947 / 4,929 uniprot IDs overexpressed in the control group compared to NMTi (P < 0.05). Arrows, mitochondrial processes significantly overrepresented in the control (DMSO) group. (B) Abundance of the mitochondrial myristoylated protein NDUFAF4 in lysates from the indicated (KL / K)MUTlung carcinoma cells treated with DMSO control or 1 μM DDD85646 (NMTi) for the indicated times analyzed by immunoblotting. (C) Representative Immunofluorescence images of (KL / K)MUTH1792 cells transiently transfected with control or NDUFAF4 specific siRNA pool were stained with the indicated antibodies 72 hours after transfection. DAPi was used to stain nuclei. Bar, 10 μm. (D) Ultrastructure of mitochondria from (KL / K)MUTH1792 cells treated with control or 1 μM DDD85646 (NMTi) for the indicate times. Arrowheads, mitochondria shown in Figure 6A. Bar, 200 nm in control 24h and 500nm in the rest. (E) Gene Ontology (GO) cellular components significantly associated with NMTi vs. DMSO by over-representation analysis of mitochondria- related proteins (Fisher’s Exact Test, P-adjusted < 0.05). Mitochondrial UniProt IDs (539 in the dataset) were queried using the Human Protein Atlas. (F) Abundance of the myristoylated outer membrane proteins TOM40, SAM50 and CHCHD3 in lysates from (KL / K)MUTlung carcinoma cells treated with DMSO control or 1 μM DDD85646 (NMTi) for the indicated times analyzed by immunoblotting. Numbers correspond to band intensity normalized to loading control. FIG.20A-20D Effect of NMTi on the abundance of TIM17A in lung carcinoma cells. A) TIM17A, TIM17B, HSP60 and TOM20 proteins analyzed by immunoblotting in lysates from Atty. Docket No.: LABIO-006WO (KL / K)MUTH1792 cells treated with 1 μM DDD85646 (NMTi) or vehicle control for the indicated times. Numbers correspond to band intensity normalized to actin loading control. B) TIM17A and SAM50 analyzed by immunoblotting in lysates from (KL / K)MUTHCC44 lung cancer cells treated with 1 μM PCLX-001 (NMTi) or vehicle control for the indicated times. Numbers correspond to band intensity normalized to GAPDH. C) TIM17A immunoblotting in lysates from (KL / K)WTlung cancer cells H522 and H1650 treated with 1 μM DDD85646 (NMTi) or vehicle control for the indicated times. Numbers correspond to band intensity normalized to actin loading control. (D) TIM17A and SAM50 analyzed by immunoblotting in lysates from H1437 (KL / K)WTlung cancer cells treated with 1 μM PCLX-001 (NMTi) or vehicle control for the indicated times. Numbers correspond to band intensity normalized to GAPDH. FIG.21A-21B Effect of lipid peroxidation on the abundance of TIM17A in lung carcinoma cells. (A) Lysates from H1792 cells treated for 3 hours with 80 μM of 4- hydroxynonenal (4-HNE) were immunoblotted with TIM17A and Tim17B antibodies. Numbers correspond to band intensity normalized to actin control. (B) Lysates from H1792 cells treated for 3 hours with 80 μM of 4-hydroxynonenal (4-HNE) were immunoblotted with PAR antibodies. Numbers correspond to band intensity normalized to actin control. DETAILED DESCRIPTION Methods of treating a subject for cancer are provided. Aspects of the methods include administering to the subject a N-myristoyltransferase inhibitor, optionally in combination with a proteasome inhibitor and / or a chemotherapeutic agent, to treat the subject for cancer. Also provided are compositions, e.g., that comprise synergistically effective amounts of a N- myristoyltransferase inhibitor and a proteasome inhibitor and / or a chemotherapeutic agent. Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges Atty. Docket No.: LABIO-006WO may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. Atty. Docket No.: LABIO-006WO While the apparatus and method has or will be described for the sake of grammatical fluidity with functional explanations, it is to be expressly understood that the claims, unless expressly formulated under 35 U.S.C. §112, are not to be construed as necessarily limited in any way by the construction of "means" or "steps" limitations, but are to be accorded the full scope of the meaning and equivalents of the definition provided by the claims under the judicial doctrine of equivalents, and in the case where the claims are expressly formulated under 35 U.S.C. §112 are to be accorded full statutory equivalents under 35 U.S.C. §112. As summarized above, methods of treating a subject for cancer are provided. By treatment, is meant that at least an amelioration of the symptoms associated with the condition afflicting the host is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., a symptom associated with the condition being treated or a side effect resulting from administration of a drug. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the host no longer suffers from the condition, or at least the symptoms that characterize the condition. Treating also includes prophylactically treating the subject, such that the liver condition does not occur in the subject. As such, treating includes preventing the occurrence of the liver condition in the subject. A variety of subjects (also referred to as “individuals”, e.g., “a subject” can also be referred to as “an individual”) are treatable according to the subject methods. Generally, such hosts are "mammals" or "mammalian," where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In many embodiments, the subjects will be humans. Aspects of embodiments of the methods include administering to the subject a N- myristoyltransferase inhibitor (NMTi). For any of the compositions and methods described herein, any convenient N-myristoyltransferase inhibitor (NMTi) may be employed. For example, NMT inhibitors described in WO 2010 / 026365 may be used. NMT inhibitors described in WO2022 / 082306 may be used. In some embodiments, the N-myristoyltransferase inhibitor is DDD85646. In some embodiments, the N-myristoyltransferase inhibitor is DDD86481 (i.e., PCLX-001 or 2,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1- Atty. Docket No.: LABIO-006WO yl)pyridin-4-yl)benzenesulfonamide). In some embodiments, the N-myristoyltransferase inhibitor is IMP-1088. Additional examples of NMT inhibitors include, but are not limited to: 2- hydroxymyristic acid, D-NMAPPD, and Tris-DBA palladium (see, e.g., Kosciuk et al., ACS Chem Biol.2020 Jul 17;15(7):1747-1758. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compositions of the present disclosure. In some embodiments, a dose of an NMTi is in the range of 0.1-60 mg / kg (e.g., 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-60 mg / kg, 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.5-60 mg / kg, 0.5-50 mg / kg, 0.5-40 mg / kg, 0.5-30 mg / kg, 1-60 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg). In some embodiments, for PCLX-001, a dose is 20mg, 40mg, 70mg, 100mg, 140mg, 210mg, or 280mg daily (e.g., oral) (or more). For example, in some cases, an oral dose can be 20 mg PCLX-001 per day, 40 mg PCLX-001 per day, 70 mg PCLX- 001 per day, 100 mg PCLX-001 per day, 140 mg PCLX-001 per day, 210 mg PCLX-001 per day, 280 mg PCLX-001 per day, 350 mg PCLX-001 per day, or 420 mg PCLX-001 per day. See, e.g., US Patent Application Publication Nos. US20250161299 and US20240350481. In certain embodiments, the subjects will be subjects that have been diagnosed for (e.g., as having a cancer such as a lung cancer, e.g., NSCLC) and are, therefore, in need of administration of the active agent. In certain embodiments, the methods may include diagnosing the subject for the presence of the disease condition (e.g., as having a cancer such as a lung cancer, e.g., NSCLC) to be treated by administration of the active agent. NMTi plus proteasome inhibitor Aspects of embodiments of the methods include administering to the subject a N- myristoyltransferase inhibitor (NMTi) and a proteasome inhibitor to treat the subject for cancer. In some embodiments (methods and / or compositions), the NMTi includes at least one of: DDD86481, DDD85646, and IMP-1088. For example, in some cases, the NMTi includes DDD86481 (also known as “PCLX-001”). In some cases, PCLX-001 is co-administered with a proteasome inhibitor such as bortezomib. For example, in some cases, a subject pharmaceutical composition includes a synergistically effective amount of an NMTi (such as PCLX-001) and a proteasome inhibitor (such as bortezomib). For any of the compositions and methods described herein, any convenient proteasome inhibitor may be employed. Proteasome inhibitors that may be employed include those described in WO2011 / 13937. Examples of proteasome inhibitors that may be employed include without limitation the following compounds, as well as pharmaceutically acceptable salts and Atty. Docket No.: LABIO-006WO boronate esters thereof: N-(4-morpholine)carbonyl- -(l -naphthyl)-L-alanine-L-leucine boronic acid, N— (8-quinoline)sulfonyl-P-(l -naphthyl)-L-alanine-L-leucine boronic acid, N-(2- pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, L-proline-L-leucine boronic acid, N- (2-quinoline)carbonyl-L-homophenylalanine-L-leucine boronic acid, N-(3-pyridine)carbonyl-L- phenylalanine-L-leucine boronic acid, N-(3-phenylpropionyl)-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4- morpholine)carbonyl-(0-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L- tyrosine-L-leucine boronic acid, and N-(4-morpholine)carbonyl-[0-(2-pyridylmethyl)]-L-tyrosine-L- leucine boronic acid. Examples of proteasome inhibitors include, but are not limited to: carfilzomib (PR-171), ixazomib, MG-132, and NPI-0052. In some instances, the proteasome inhibitor is bortezomib (PS-341, Velcade, MLN-341, LDP-341). In some instances, the proteasome inhibitor is ixazomib. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compositions of the present disclosure. In some embodiments, a dose of a proteasome inhibitor is in the range of 0.1-60 mg / kg (e.g., 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-60 mg / kg, 0.1-50 mg / kg, 0.1- 40 mg / kg, 0.1-30 mg / kg, 0.5-60 mg / kg, 0.5-50 mg / kg, 0.5-40 mg / kg, 0.5-30 mg / kg, 1-60 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg). In some embodiments, bortezomib can be administered at a dose in a range of from 0.5-2 mg / m2(e.g., 0.5-1.8, 0.5-1.7, 0.5-1.6, 0.5-1.5, 0.5-1.4, 0.5-1.3, 0.6-2, 0.6-1.8, 0.6-1.7, 0.6-1.6, 0.6-1.5, 0.6-1.4, 0.6-1.3, 0.7-2, 0.7-1.8, 0.7-1.7, 0.7-1.6, 0.7-1.5, 0.7-1.4, 0.7-1.3, 0.8-2, 0.8-1.8, 0.8-1.7, 0.8-1.6, 0.8-1.5, 0.8-1.4, 0.8-1.3 mg / m2)(e.g., by IV). In some embodiments, bortezomib can be administered at a dose of about 1.3 mg / m2(e.g., by IV) (see, e.g., US Patent Application Publication No. US20200392242). In some embodiments, bortezomib can be administered at a dose of about 1.6 mg / m2(e.g., by IV). In some embodiments, bortezomib can be administered at a dose in a range of from 0.8-1.6 mg / m2. As such, in some cases, the NMTi includes PCLX-001 and the proteasome inhibitor includes bortezomib. In some cases, the NMTi includes DDD85646 and the proteasome inhibitor includes bortezomib. In some cases, the NMTi includes IMP-1088 and the proteasome inhibitor includes bortezomib. In some cases, the NMTi includes PCLX-001 and the proteasome inhibitor includes ixazomib. In some cases, the NMTi includes DDD85646 and the proteasome inhibitor includes ixazomib. In some cases, the NMTi includes IMP-1088 and the proteasome inhibitor includes ixazomib. Atty. Docket No.: LABIO-006WO NMTi and KRAS / LKB / KEAP1 mutational signature In some embodiments, a subject method is a method of killing an apoptosis-resistant lung carcinoma cell, where the cell is contacted with an NMTi (e.g., DD85646, DDD86481, IMP- 1088). The cell can be in vitro (e.g., in cell culture). The cell can be in vivo. As such, in some embodiments, a subject method is a method of treating a subject for therapy resistant lung cancer, where an NMTi is administered to the subject (e.g., DD85646, DDD86481, IMP-1088). In some embodiments, the apoptosis-resistant lung carcinoma cell includes a KRAS / LKB / KEAP1 mutational signature. In some embodiments, a subject who is being treated has a therapy-resistant lung cancer characterized by the presence of apoptosis-resistant lung cancer cells that have a KRAS / LKB / KEAP1 mutational signature. In either scenario, in some cases, a subject method includes a determination of whether the cell / subject has a KRAS / LKB / KEAP1 mutational signature. A KRAS / LKB / KEAP1 mutational signature refers to the cell having a KRAS mutation in combination with a mutation in LKB1 and / or a mutation in KEAP1 (see, e.g., US Patent Nos. US12371507 and US11260062). As such, KRAS / LKB / KEAP1 mutational signature can be: (i) a KRAS mutation plus an LKB1 mutation; or (ii) a KRAS mutation plus a KEAP1 mutation; or (iii) a KRAS mutation plus a LKB1 mutation and a KEAP1 mutation). In other words, the term “KRAS / LKB / KEAP1 mutational signature” as used herein refers cells / subjects that have a KRAS mutation and also have a mutation in LKB1 and / or KEAP1. In other words, the cells / subject have the following possible combinations of mutations: (1) KRAS / LKB1 (a KRAS mutation and an LKB1 mutation), (2) KRAS / KEAP1 (a KRAS mutation and a KEAP1 mutation), (3) KRAS / LKB1 / KEAP1 (a KRAS mutation, an LKB1 mutation, and a KEAP1 mutation). NSCLCs with KRAS and LKB1 (also referred to as STK11) concurrent mutations have extensive metabolic reprogramming and are resistant to most treatments, including immunocheckpoint inhibitors. KEAP1 mutations are commonly concurrent with KRAS and / or LKB1 mutations in NSCLC and confer tolerance to oxidative stress through the KEAP1 / NRF2 pathway, promoting tumor progression and drug resistance. KRAS, LKB1, KEAP1 triple mutant tumors exhibit extensive metabolic reprogramming, are highly resistant to chemotherapy, and have poor responses to immunocheckpoint inhibitors. KRAS (Uniprot P01116) mutations can include any KRAS mutation associated with cancer (e.g., lung cancer) – such mutations are known in the art (see, e.g., Mondal et al., Cells. 2024 Jul 19;13(14):1221). Examples include but are not limited to those listed in Table 1. Atty. Docket No.: LABIO-006WO Table 1. Examples of KRAS mutations associated with cancer (see, e.g., Mondal et al., Cells. 2024 Jul 19;13(14):1221) Type of Cancer KRAS Mutation (Relative Frequency in Percentages) , A ), T , C , , V Atty. Docket No.: LABIO-006WO Cutaneous Melanoma G12D (12.5), G12R (12.5), G13D (25.0), K117N (12.5), M72K (12.5), S122F (12.5), L25R (12.5) Atty. Docket No.: LABIO-006WO Glioblastoma Multiforme G12D (100.0) nction mutation) can include any LKB1 mutation, e.g., a mutation associated with cancer (e.g., lung cancer) – examples of such mutations are known in the art (see, e.g., Chen et al., Ann Transl Med.2020 Feb;8(4):141; Dziadziuszko et al., J Thorac Oncol.2022 Mar;17(3):351-352; and Sanchez-Cespedees et al. (2002) Cancer Res.62: 3659-3662). Kelch-like ECH-associated protein-1 (KEAP1) (Uniprot Q14145) mutations (e.g., a loss- of-function mutation) can include any KEAP1 mutation, e.g., a mutation associated with cancer (e.g., lung cancer) – examples of such mutations are known in the art (see, e.g., Islam et al., Cell Death Dis 13, 696 (2022); Chen et al., Ann Transl Med.2020 Feb;8(4):141; and Dziadziuszko et al., J Thorac Oncol.2022 Mar;17(3):351-352; and Singh et al. (2006) PLoS Med 3: e420). In some embodiments, the cancer / cell is identified as having wild-type LKB1, but mutated KEAP1. In some embodiments, the cancer / cell is identified as having wild-type KEAP1, but mutated LKB1. In some embodiments, the cancer / cell is identified as having a mutated LKB1 and mutated KEAP1. The term “loss-of-function mutation” as used herein refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological activity or enzymatic activity), results in expression of only a fragment of the protein that no longer exhibits wild-type activity, or results in no expression of the wild-type protein. For example, a loss- of-function mutation affecting LKB1 in a cell may result in the loss of expression of the LKB1 protein, expression of only a fragment of the LKB1 protein, or expression of the LKB1 protein that exhibits diminished or no enzymatic activity (e.g., no serine / threonine kinase enzymatic activity) in the cancerous cell. Similarly, a loss-of-function mutation affecting KEAP1 in a cell may result in the loss of expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits diminished or no activity. Determination of whether or not a given cell / subject has a KRAS / LKB / KEAP1 mutational signature can be accomplished using any convenient method and multiple such methods will be known to one of ordinary skill in the art. Determining whether a tumor or cancer comprises a mutation can be undertaken, for example, by assessing the nucleotide sequence encoding the protein or by assessing the amino acid sequence of the protein. Methods for detecting a mutation include, but are not limited to, polymerase chain reaction-restriction fragment length Atty. Docket No.: LABIO-006WO polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele- specific PCR amplification (MASA) assays, direct and / or next generation-based sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, detection of a mutant can use a binding agent (e.g., an antibody) specific for the mutant protein. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using array-based methods. As an example, RNA or DNA sequencing of KRAS and (LKB1 and / or KEAP1) can be performed to determine whether there are mutations (e.g., known cancer associated mutations) in the coding sequence and / or mutations in the corresponding genetic locus (e.g., mutations in a promoter and / or enhancer). When determining whether cancer cells from an individual have a KRAS / LKB / KEAP1 mutational signature, such an analysis can be performed on a biological sample, e.g., a blood sample, or biopsy, e.g., a lung biopsy. As would be understood by one of ordinary skill in the art, in some cases, a control (non-cancer) biological sample from an individual may not have a KRAS / LKB / KEAP1 mutational signature while another biological sample from that same individual, e.g., from the cancer (e.g., a biopsy such as a lung biopsy) does have the KRAS / LKB / KEAP1 mutational signature. Methods for determining whether a tumor or cancer comprises a mutation can use a variety of biological samples. In some embodiments, the biological sample is taken from a patient having a tumor or cancer. In some embodiments, the biological sample is a fresh tumor / cancer sample. In some embodiments, the biological sample is a frozen tumor / cancer sample. In some embodiments, the biological sample is a formalin-fixed paraffin-embedded (FFPE) sample. In some embodiments, the biological sample is a circulating cell-free DNA and / or circulating tumor cell (CTC) sample. In some embodiments, the biological sample is processed to a cell lysate. In some embodiments, the biological sample is processed to DNA or RNA. In a certain embodiment, the biological sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles. In some embodiments, a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess mutation status. In some embodiments, the biological sample is a lung biopsy. Atty. Docket No.: LABIO-006WO NMTi and TIM17A dependence In some embodiments (methods and / or compositions), a subject method is a method of killing lung cancer cell (e.g., a lung cancer cells such as an NSCLC cell), where the method includes contacting the lunger cancer cell with an NMTi (such as DDD85646, DDD86481, or IMP-1088), wherein the lung cancer cell is TIM17A dependent. In some cases, the NMTi includes PCLX-001. The cell can be in vitro (e.g., in cell culture). The cell can be in vivo. As such, in some embodiments, a subject method is a method of treating a subject for lung cancer (e.g., a lung cancer such as NSCLC), where the method includes administering an NMTi (such as DDD85646, DDD86481, or IMP-1088), wherein the lung cancer is TIM17A dependent. In some cases, the NMTi includes PCLX-001. In some cases, a subject method includes determining that the lung cancer (or lung cancer cell) exhibits TIM17A dependence prior to the contacting, or prior to the administering. In some cases, a subject method includes determining that the lung cancer (or lung cancer cell) exhibits increased TIM17A dependence relative to a control, prior to the contacting, or prior to the administering. TIM17A is the mitochondrial transporter: Translocase of Inner Mitochondrial Membrane 17 homologue A. TIM17 subunits A and B are essential components of the TIM23 inner mitochondrial membrane translocase, one of the two complexes that import nuclear-encoded proteins to the mitochondria. As noted above, in some embodiments (methods and / or compositions), a lung cancer cell is TIM17A dependent (i.e., exhibits TIM17A dependence). For example, in some cases, a subject has a TIM17A dependent lung cancer (i.e., a lung cancer that exhibits TIM17A dependence). In some cases, a cancer cell that exhibits TIM17A dependence has a KRAS / LKB / KEAP1 mutational signature. As demonstrated in the working examples herein, contacting lung cancer cells with NMTi causes a decrease in TIM17A levels. In other words, the amount of TIM17A present in a cell (i.e., TIM17A protein level), is reduced by NMTi treatment. However, not all cells are sensitive to NMTi treatment. Those cells that are TIM17A dependent are sensitive to NMTi treatment, while those cells that are TIM17A independent are not sensitive (i.e. are resistant) to NMTi treatment – despite the fact that TIM17A levels decrease in both types of cells as a result of contact with NMTi (i.e., NMTi treatment). As such, in some cases, a cancer cell (e.g., cancer cells from a biological sample from a subject) is tested for TIM17A dependence to determine whether the cancer / cancer cell will respond to NMTi (i.e., whether the cancer / cancer cell is sensitive to NMTi). Cancers / cells determined to be TIM17A dependent can therefore be determined to be treatable with (i.e., sensitive to) NMTi. Atty. Docket No.: LABIO-006WO As demonstrated in the working examples below, a dependency score for TIM17A can be used to determine whether a given cell is TIM17A dependent. For example, the inventors used the Cancer Dependency Map portal (CRISPR Chronos algorithm), which assigns an estimated CRISPR DepMap Score for each gene in a way that negative values suggest decreased cell viability. The inventors determined that TIM17A dependency scores for NMTi sensitive cells HCC44, H460 and H1792 were lower (decreased cell viability; more TIM17A dependent) when compared with the dependency scores of resistant cells H522, H1650 and H1437. Thus, dependency scores for TIM17A for a given cell type / line of interest can be used to determine if that cell exhibits TIM17A dependence – and therefore to determine if that call is NMTi sensitive. As another example, and also as demonstrated in the working examples below, TIM17A levels can be reduced (e.g., using RNAi agent such as siRNA or shRNA), and cell viability can be assayed, e.g., using cell death assays. In some embodiments, TIM17A levels can be reduced (e.g., using RNAi agent such as siRNA or shRNA), and colony formation ability can be assayed. The results can be compared to an appropriate control, e.g., results can be compared to results from using cells known to be either TIM17A dependent or independent. TIM17A levels can be reduced using any convenient method, and many such methods will be known to one of ordinary skill in the art. Examples of such methods include, but are not limited to: RNAi, siRNA, shRNA, CRISPRi (i.e., CRISPR-based inhibition, e.g., using a transcription inhibiting CRISPR system to reduce expression of TIM17A), and CRISPR nuclease (e.g., to genetically knockdown TIM17A). When determining whether cancer cells exhibit TIM17A dependence, such an analysis can be performed on a biological sample, e.g., a blood sample, or biopsy, e.g., a lung biopsy. As would be understood by one of ordinary skill in the art, in some cases, a control (non-cancer) biological sample from an individual may not exhibit TIM17A dependence while another biological sample from that same individual, e.g., from the cancer (e.g., a biopsy such as a lung biopsy) does exhibit TIM17A dependence. Methods for determining whether a tumor or cancer exhibits TIM17A dependence can use a variety of biological samples. In some embodiments, the biological sample is taken from a patient having a tumor or cancer. In some embodiments, the biological sample is a fresh tumor / cancer sample. In some embodiments, the biological sample is processed to a cell lysate. In a certain embodiment, the biological sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles. In some Atty. Docket No.: LABIO-006WO embodiments, a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess TIM17A dependence. In some embodiments, the biological sample is a lung biopsy. NMTi and a chemotherapeutic agent In some embodiments (methods and / or compositions), a subject method is a method of treating a subject for cancer (e.g., a lung cancer such as NSCLC), where the method includes administering an NMTi (such as DDD85646, DDD86481, or IMP-1088) and a chemotherapeutic agent (such as a DNA damaging chemotherapeutic agent) to the subject. In some cases, the NMTi includes PCLX-001 and the chemotherapeutic agent includes pemetrexed and a platinum- based compound (e.g., cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, lobaplatin). In some such cases, the chemotherapeutic agent includes pemetrexed and cisplatin. For any of the compositions and methods described herein, any convenient chemotherapeutic agent can be used. In some cases, a chemotherapeutic agent is a DNA damaging chemotherapeutic agent. Examples of DNA damaging chemotherapeutic agents include, but are not limited to: cisplatin, carboplatin, oxaliplatin, methotrexate, doxorubicin, and daunorubicin (see, e.g., Cheung-Ong et al., Chem Biol.2013 May 23;20(5):648-59). In some embodiments, a chemotherapeutic agent (e.g., a DNA damaging chemotherapeutic agent) includes pemetrexed. In some embodiments, a chemotherapeutic agent (e.g., a DNA damaging chemotherapeutic agent) includes pemetrexed and cisplatin. In some embodiments, a chemotherapeutic agent (e.g., a DNA damaging chemotherapeutic agent) includes pemetrexed and carboplatin. In some cases, the chemotherapeutic agent includes one or more (e.g., 1, 2, two or more, or three or more) platinum-based compounds. In some cases, the chemotherapeutic agent includes two platinum-based compounds. Platinum-based compounds will be known to one of ordinary skill in the art. Examples of platinum-based compounds include, but are not limited to: cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin (a cisplatin derivative), and lobaplatin (D-19466). In some embodiments, the chemotherapeutic agent includes cisplatin. In some embodiments, the chemotherapeutic agent includes cisplatin. In some embodiments, the chemotherapeutic agent includes carboplatin. In some embodiments, the chemotherapeutic agent includes oxaliplatin. In some embodiments, the chemotherapeutic agent includes picoplatin. In some embodiments, the chemotherapeutic agent includes nedaplatin. In some embodiments, the chemotherapeutic agent includes lobaplatin. In some cases, pemetrexed can be used in combination with a platinum-based compound (e.g., cisplatin, carboplatin). As such, in some cases, the chemotherapeutic agent Atty. Docket No.: LABIO-006WO includes pemetrexed and cisplatin. In some cases, the chemotherapeutic agent includes pemetrexed and carboplatin. In some cases, the chemotherapeutic agent includes pemetrexed and oxaliplatin. In some cases, the chemotherapeutic agent includes pemetrexed and picoplatin. In some cases, the chemotherapeutic agent includes pemetrexed and nedaplatin. In some cases, the chemotherapeutic agent includes pemetrexed and lobaplatin. Chemotherapeutic agents that find use in the present disclosure include, without limitation, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus) , Afinitor Disperz (Everolimus) , Alimta (PEMETREXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone), Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), lclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado-trastuzumab Emtansine), Kyprolis (Carfilzomib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Atty. Docket No.: LABIO-006WO Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Panretin (Alitretinoin), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar (Streptozocin), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zytiga (Abiraterone), Nimotuzumab and immune checkpoint inhibitors such as nivolumab, pembrolizumab / MK-3475, pidilizumab and AMP-224 targeting PD-1; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting PD-L1 and those targeting CTLA-4 such as ipilimumab. Atty. Docket No.: LABIO-006WO A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compositions of the present disclosure. In some embodiments, a dose of a cisplatin is in the range of 15-85 mg / m2(e.g., 15-80, 15-75, 15-50, 15-40, 15-30, 15-25, 20-85, 20-80, 20-75, 20-50, 20-40, 20-30, 20- 25, 25-85, 25-80, 25-75, 25-50, 25-40, 25-30 mg / m2)(e.g., by IV). In some embodiments, cisplatin can be administered at a dose of about 25 mg / m2(e.g., by IV). In some embodiments, cisplatin can be administered at a dose of about 75 mg / m2(e.g., by IV). In some embodiments, a dose of a Carboplatin is about area under curve (AUC) = 5 mg / ml / min (e.g., IV). In some embodiments, a dose of a Pemetrexed is in the range of 400-600 mg / m2(e.g., 400-550, 400- 525, 400-500, 450-600, 450-550, 450-525, 450-500, 475-600, 475-550, 475-525, 475-500, 500- 600, 500-550 mg / m2)(e.g., by IV). In some embodiments, Pemetrexed can be administered at a dose of about 500 mg / m2(e.g., by IV). Co-administration and synergy Many of the effective combinations of N-myristoyltransferase (NMTi) plus another compound / agent, e.g., a proteasome inhibitor and / or a chemotherapeutic agent, are attributable at least in part to functional synergy between the compounds / agents. For example, many of the effective combinations of N-myristoyltransferase (NMTi) and proteasome inhibitors are attributable at least in part to functional synergy between the two compounds. Synergy between agents (e.g., inhibitors) may be direct or indirect, leading to desired activity. In some embodiments, the NMTi is DDD86481 (also known as “PCLX-001”) and the proteasome inhibitor is bortezomib. In some embodiments, the NMTi is DDD85646 and the proteasome inhibitor is bortezomib. In some embodiments, the NMTi is IMP-1088 and the proteasome inhibitor is bortezomib. To quantify the degree of synergy of a combination of candidate agents (e.g., an NMTi and a proteasome inhibitor, or an NMTi and a chemotherapeutic agent), the combination response can be compared against an expected combination response, under the assumption of non-interaction calculated using a reference model (Tang J. et al. (2015) What is synergy? The saariselkä agreement revisited. Front. Pharmacol., 6, 181). Commonly-utilized reference models can include, for example, the highest single agent (HSA) model, where the synergy score quantifies the excess over the highest single drug response (Berenbaum M.C. (1989) What is synergy. Pharmacol. Rev., 41, 93–141); the Loewe additivity model, where the synergy score quantifies the excess over the expected response if the two drugs are the same compound (Loewe S. (1953) The problem of synergism and antagonism of combined drugs. Atty. Docket No.: LABIO-006WO ArzneimiettelForschung, 3, 286–290); the Bliss independence model, where the expected response is a multiplicative effect as if the two drugs act independently (Bliss C.I. (1939) The toxicity of poisons applied jointly. Ann. Appl. Biol., 26, 585–615); or the Zero interaction potency (ZIP) model, where the expected response corresponds to an additive effect as if the two drugs do not affect the potency of each other (Yadav B. et al. (2015) Searching for drug synergy in complex dose–response landscapes using an interaction potency model. Comput. Struct. Biotechnol. J., 13, 504–505). To facilitate data processing of the active agent dose-response matrices performed using different doses of tested combinations of N-myristoyltransferase inhibitors and another agent (e.g., proteasome inhibitor, chemotherapeutic agent, and the like) on cells, the user may employ an algorithm that uses key functions of R-package, called SynergyFinder. For example, to facilitate data processing of the active agent dose-response matrices performed using different doses of tested combinations of N-myristoyltransferase inhibitors and proteasome inhibitors on cells, the user may employ an algorithm that uses key functions of R-package, called SynergyFinder. This algorithm is described by Ianevski A. et al. (2017) SynergyFinder: a web application for analyzing drug combination dose–response matrix data. Bioinformatics. Aug 1; 33(15): 2413–2415. The algorithm is publicly available from the Netherlands Translational Research Center, and can be accessed via the Internet. User instructions and tutorials of the SynergyFinder package have been published by He, Wennerberg, Aittokallio and Tang in 2016, updated 2018. Unless explicitly stated or otherwise required, effective combinations of agents according to this invention do not necessarily require measurable synergy at the target engagement level in experiments done in vitro in order to be effective for particular purposes in vivo. For example, unless explicitly stated or otherwise required, effective combinations of inhibitors according to this invention do not necessarily require measurable synergy at the target engagement level in experiments done in vitro in order to be effective for particular purposes in vivo. However, the user may find it useful to screen for effective combinations by calculating inhibition interactions according to the HAS model, the Loewe additivity model, the Bliss independence model, or the ZIP model. Reference in this disclosure to a delta (“d”) synergy coefficient or index refers to the d value calculated according to the ZIP model of Yadav et al., supra. Using this model, the larger the d value, the stronger the synergistic anti-tumor effects. Any d value larger than 0 shows positive synergy. The d values given in the experimental sections below were calculated using the ZIP model. Effective combinations N-myristoyltransferase and proteasome inhibitors and Mcl-1 inhibitors according to this invention may have a d value, or synergy coefficient that is Atty. Docket No.: LABIO-006WO greater than 5, 10, 15, 20, 30, 50, 80, or 150. Expressed in ranges, the synergy between such compounds may have d values in the range of 1-500, 10-100, or 20-100. As summarized above, methods of treating cancer (e.g., a lung cancer such as NSCLC) are provided. Aspects of the methods include administration to the subject of a N- myristoyltransferase (NMTi) in combination with a proteasome inhibitor. The two inhibitors may be administered concurrently, e.g., where they may be administered simultaneously, e.g., in discrete compositions or combined in a single composition. Alternatively, the two inhibitors may be administered sequentially, e.g., where the N-myristoyltransferase inhibitor is administered before the proteasome inhibitor or the N-myristoyltransferase is administered after the proteasome inhibitor. In embodiments, the two inhibitors can be administered at the same time, e.g., as two separate formulations, or combined into a single composition. Alternately, the two inhibitors agent can be administered sequentially to the subject in different formulations. Regardless of whether the inhibitors are administered sequentially or simultaneously, or any effective variation thereof, the agents are considered to be administered together or in combination for purposes of the present invention. Routes of administration of the two agents may vary. Representative routes of administration are described elsewhere herein. Likewise, aspects of the methods include administration to the subject of a N- myristoyltransferase (NMTi) in combination with a chemotherapeutic agent, e.g., a DNA damaging chemotherapeutic agent, which can include, e.g., pemetrexed plus one or more platinum-based compounds such as cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, or lobaplatin. The agents (the NMTi such as PCLX-001, and the chemotherapeutic agent) may be administered concurrently, e.g., where they may be administered simultaneously, e.g., in discrete compositions or combined in a single composition. Alternatively, the agents may be administered sequentially, e.g., where the N-myristoyltransferase inhibitor is administered before the chemotherapeutic agent or the N-myristoyltransferase is administered after the chemotherapeutic agent. In embodiments, the agents can be administered at the same time, e.g., as separate formulations, or combined into a single composition. Alternately, the agents can be administered sequentially to the subject in different formulations. Regardless of whether the agents are administered sequentially or simultaneously, or any effective variation thereof, the agents are considered to be administered together or in combination for purposes of the present disclosure. Routes of administration of the agents may vary. Representative routes of administration are described elsewhere herein. When two or more agents are administered combination (e.g., administered sequentially or simultaneously), this can also be referred to as co-administration. The terms "co- Atty. Docket No.: LABIO-006WO administration", “co-administer”, and "in combination with" include the administration of two or more therapies either simultaneously, concurrently or sequentially within no specific time limits. In some embodiments, agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time. In some embodiments, therapeutic agents are in the same composition or unit dosage form. In other embodiments, therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first therapy (e.g., agent) can be administered prior to (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., agent). In some cases, an agent (e.g., an NMTi) is co-administered with an agent or therapy such as those listed elsewhere herein, to treat cancer (e.g., a lung cancer such as NSCLC). Such administration may involve concurrent (i.e. at the same time), prior, or subsequent administration of the agent and / or therapy with respect to the administration of an agent or agents of the disclosure. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular agents and compositions of the present disclosure. In some instances, methods of treating cancer are provided. The term “cancer”, as used herein, refers to a variety of conditions caused by the abnormal, uncontrolled growth of cells. Cells capable of causing cancer, referred to as “cancer cells”, possess characteristic properties such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain typical morphological features. Cancer cells may be in the form of a tumor, but such cells may also exist alone within a subject, or may be a non-tumorigenic cancer cell. A cancer can be detected in any of a number of ways, including, but not limited to, detecting the presence of a tumor or tumors (e.g., by clinical or radiological means), examining cells within a tumor or from another biological sample (e.g., from a tissue biopsy), measuring blood markers indicative of cancer, and detecting a genotype indicative of a cancer. However, a negative result in one or more of the above detection methods does not necessarily indicate the absence of cancer, e.g., a patient who has exhibited a complete response to a cancer treatment may still have a cancer, as evidenced by a subsequent relapse. Atty. Docket No.: LABIO-006WO Cancers, the treatment of which may include the use synergistically effective amounts of a N-myristoyltransferase inhibitor and a proteasome inhibitor, will vary and may include but are not limited to e.g., Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS-Related Cancers (e.g., Kaposi Sarcoma, Lymphoma, etc.), Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid / Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (Extrahepatic), Bladder Cancer, Bone Cancer (e.g., Ewing Sarcoma, Osteosarcoma and Malignant Fibrous Histiocytoma, etc.), Brain Stem Glioma, Brain Tumors (e.g., Astrocytomas, Central Nervous System Embryonal Tumors, Central Nervous System Germ Cell Tumors, Craniopharyngioma, Ependymoma, etc.), Breast Cancer (e.g., female breast cancer, male breast cancer, childhood breast cancer, etc.), Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor (e.g., Childhood, Gastrointestinal, etc.), Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Central Nervous System (e.g., Atypical Teratoid / Rhabdoid Tumor, Embryonal Tumors, Germ Cell Tumor, Lymphoma, etc.), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Neoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Duct (e.g., Bile Duct, Extrahepatic, etc.), Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (e.g., Intraocular Melanoma, Retinoblastoma, etc.), Fibrous Histiocytoma of Bone (e.g., Malignant, Osteosarcoma, etc.), Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (e.g., Extracranial, Extragonadal, Ovarian, Testicular, etc.), Gestational Trophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis (e.g., Langerhans Cell, etc.), Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (e.g., Pancreatic Neuroendocrine Tumors, etc.), Kaposi Sarcoma, Kidney Cancer (e.g., Renal Cell, Wilms Tumor, Childhood Kidney Tumors, etc.), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (e.g., Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell, etc.), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (e.g., Non-Small Cell, Small Cell, etc.), Lymphoma (e.g., AIDS- Related, Burkitt, Cutaneous T-Cell, Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), etc.), Macroglobulinemia (e.g., Waldenström, etc.), Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel Cell Carcinoma, Atty. Docket No.: LABIO-006WO Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma / Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myelogenous Leukemia (e.g., Chronic (CML), etc.), Myeloid Leukemia (e.g., Acute (AML), etc.), Myeloproliferative Neoplasms (e.g., Chronic, etc.), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non- Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer (e.g., Lip, etc.), Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (e.g., Epithelial, Germ Cell Tumor, Low Malignant Potential Tumor, etc.), Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Pleuropulmonary Blastoma, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (e.g., Ewing, Kaposi, Osteosarcoma, Rhabdomyosarcoma, Soft Tissue, Uterine, etc.), Sézary Syndrome, Skin Cancer (e.g., Childhood, Melanoma, Merkel Cell Carcinoma, Nonmelanoma, etc.), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer (e.g., with Occult Primary, Metastatic, etc.), Stomach (Gastric) Cancer, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Ureter and Renal Pelvis Cancer, Urethral Cancer, Uterine Cancer (e.g., Endometrial, etc.), Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenström Macroglobulinemia, Wilms Tumor, and the like. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is NSCLC. Likewise, cancers, the treatment of which may include the use synergistically effective amounts of a N-myristoyltransferase inhibitor (NMTi) and a chemotherapeutic agent (described elsewhere herein), will vary and may include but are not limited to the same list as above (see preceding paragraph). Likewise, cancers, the treatment of which may include the use an NMTi after determination that the cancer / cancer cells have a KRAS / LKB / KEAP1 mutational signature, will vary and may include but are not limited to the same list as above (see preceding paragraph). Likewise, cancers, the treatment of which may include the use an NMTi after determination that the cancer / cancer cells exhibit TIM17A dependence, will vary and may include but are not limited to the same list as above (see preceding paragraph). Atty. Docket No.: LABIO-006WO Also provided are compositions for practicing the methods described in the present disclosure. In general, subject compositions may have synergistically effective amounts of a N- myristoyltransferase inhibitor and a proteasome inhibitor, e.g., as described above, in addition to a pharmaceutically acceptable excipient. Likewise, subject compositions may have effective amounts (e.g., synergistically effective amounts) of a N-myristoyltransferase inhibitor (e.g., PCLX-001) and a chemotherapeutic agent such as a DNA damaging chemotherapeutic agent, e.g., as described above (such as Pemetrexed plus cisplatin), in addition to a pharmaceutically acceptable excipient. Subject compositions may have effective amounts of a N- myristoyltransferase inhibitor (e.g., PCLX-001), e.g., as described above, in addition to a pharmaceutically acceptable excipient. In some embodiments, the subject compositions contain a secondary agent for treating any of the diseases or conditions described above. Also provided are kits for practicing the methods described in the present disclosure. For example, in some cases, in addition to a subject composition (e.g., (1) an NMTi; (2) an NMTi and a proteasome inhibitor; or (3); an NMTi and a chemotherapeutic agent), a kit includes materials / reagents for assessing whether a cancer / cancer cell comprises a KRAS / LKB / KEAP1 mutational signature. In some cases, in addition to a subject composition (e.g., (1) an NMTi; (2) an NMTi and a proteasome inhibitor; (3); an NMTi and a chemotherapeutic agent), a kit includes materials / reagents for assessing whether a cancer / cancer cell exhibits TIM17A dependence. Compositions of the present disclosure can be administered by any suitable means, including topical, oral, parenteral, intrapulmonary, and intranasal. Parenteral infusions include intramuscular, intravenous (bolus or slow drip), intraarterial, intraperitoneal, intrathecal or subcutaneous administration. An agent can be administered in any manner which is medically acceptable. This may include injections, by parenteral routes such as intravenous (IV), intravascular, intraarterial, subcutaneous, intramuscular, intratumor, intraperitoneal, intraventricular, intraepidural, or others as well as oral, nasal, ophthalmic, rectal, or topical. Sustained release administration is also specifically included in the disclosure, by such means as depot injections or erodible implants. As noted above, active agents can be formulated with a pharmaceutically acceptable carrier (one or more organic or inorganic ingredients, natural or synthetic, with which a subject agent is combined to facilitate its application). A suitable carrier includes sterile saline although other aqueous and non-aqueous isotonic sterile solutions and sterile suspensions known to be pharmaceutically acceptable are known to those of ordinary skill in the art. An "effective amount" refers to that amount which is capable of ameliorating or delaying progression of the diseased, degenerative or damaged condition. An effective amount can be determined on an Atty. Docket No.: LABIO-006WO individual basis and will be based, in part, on consideration of the symptoms to be treated and results sought. An effective amount can be determined by one of ordinary skill in the art employing such factors and using no more than routine experimentation. The composition may be administered in a unit dosage form and may be prepared by any methods well known in the art. Such methods include combining agent with a pharmaceutically acceptable carrier or diluent which constitutes one or more accessory ingredients. A pharmaceutically acceptable carrier is selected on the basis of the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used. Depending on the individual and condition being treated and on the administration route, the active agent may be administered in dosages of 0.01 mg to 500 mg / kg body weight per day, e.g. about 20 mg / day for an average person. Dosages will be appropriately adjusted for pediatric formulation. In some embodiments, the composition is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from 5 mM to 100 mM. In some embodiments, the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride, and sugars e.g., mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further includes a non-ionic surfactant such as polysorbate 20 or 80. Optionally the composition may further include a preservative. Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the composition is stored at about 4ºC. Pharmaceutical compositions may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored over extended periods of time, even at ambient temperatures. Compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The preparation also can be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above. Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-119, 1997. The compositions of this invention can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to Atty. Docket No.: LABIO-006WO permit a sustained or pulsatile release of the active ingredient. The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration. As described above, the composition may also contain a secondary agent for treatment of any of the diseases or condition described above. When the disease or condition is cancer, the secondary agent may be a chemotherapeutic agent. Chemotherapeutic agents that find use in the present disclosure include, without limitation, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus) , Afinitor Disperz (Everolimus) , Alimta (PEMETREXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone), Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), lclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado-trastuzumab Emtansine), Kyprolis (Carfilzomib), Leukeran Atty. Docket No.: LABIO-006WO (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Panretin (Alitretinoin), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar (Streptozocin), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zytiga (Abiraterone), Nimotuzumab and immune checkpoint inhibitors such as nivolumab, pembrolizumab / MK-3475, pidilizumab and Atty. Docket No.: LABIO-006WO AMP-224 targeting PD-1; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting PD-L1 and those targeting CTLA-4 such as ipilimumab. EXEMPLARY NON-LIMITING ASPECTS OF THE DISCLOSURE DESCRIPTION Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to those of ordinary skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below. It will be apparent to one of ordinary skill in the art that various changes and modifications can be made without departing from the spirit or scope of the invention. 1. A method of treating a subject for cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor and a proteasome inhibitor to treat the subject for cancer. 2. The method according to 1, wherein the N- myristoyltransferase inhibitor is DDD86481. 3. The method according to 1 or 2, wherein the proteasome inhibitor is bortezomib. 4. The method according to any of the preceding claims, wherein the N- myristoyltransferase inhibitor and proteasome inhibitor are administered to the subject simultaneously. 5. The method according to 4, wherein the N-myristoyltransferase inhibitor and a proteasome inhibitor are administered to the subject in a single pharmaceutical composition. 6. The method according to any of 1 to 3, wherein the N-myristoyltransferase inhibitor and proteasome inhibitor are administered to the subject sequentially. 7. The method according to any of the preceding claims, wherein the subject is a mammal. 8. The method according to 7, wherein the mammal is a human. 9. The method according to any of the preceding claims, wherein the cancer is lung cancer. 10. A pharmaceutical composition comprising a synergistically effective amount of a N-myristoyltransferase inhibitor and a proteasome inhibitor. Atty. Docket No.: LABIO-006WO 11. The pharmaceutical composition according to 10, wherein the N- myristoyltransferase inhibitor is selected from DDD85646, DDD86481 and IMP-1088. 12. The pharmaceutical composition according to 10, wherein the N- myristoyltransferase inhibitor is DDD86481. 13. The pharmaceutical composition according to any one of 10-12, wherein the proteasome inhibitor is bortezomib. 14. A method of killing an apoptosis-resistant lung carcinoma cell, the method comprising: contacting the cell with a N-myristoyltransferase inhibitor to kill the apoptosis- resistant lung carcinoma cell. 15. The method according to 14, wherein the method results in one or more of mitochondrial ferrous iron overload, increased ROS generation, excessive lipid peroxidation and PARP activation in the apoptosis-resistant lung carcinoma cell. 16. The method according to any of 14 to 15, wherein the killing comprises parthanatos. 17. The method according to any of 14-16, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481 and IMP-1088. 18. The method according to any of 14-17, wherein the apoptosis-resistant lung carcinoma cell comprises a KRAS / LKB / KEAP1 mutational signature. 19. The method according to any of 14-18, wherein the apoptosis resistant lung carcinoma cell exhibits increased dependency on TIM17A relative to a control. 20. The method according to any of 14-18, wherein the method comprises, prior to said contacting, determining that the lung carcinoma cell exhibits increased TIM17A dependence relative to a control. 21. The method according to any of 14-20, wherein the method further comprises contacting the cell with a chemotherapeutic agent. 22. The method according to 21, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent. 23. The method according to 22, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof. 24. The method according to 21, wherein the chemotherapeutic agent comprises one or more platinum-based compounds. 25. The method according to 21, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound. Atty. Docket No.: LABIO-006WO 26. The method according to any of 14-25, wherein the cell is in vivo and the method comprises administering the N-myristoyltransferase inhibitor to a subject comprising the cell. 27. The method according to 26, wherein the subject is a mammal. 28. The method according to 27, wherein the mammal is a human. 29. The method according to any of 14-25, wherein the cell is in vitro. 30. The method according to any of 14-29, wherein the apoptosis-resistant lung carcinoma cell is non-small cell lung carcinoma (NSCLC) cell. 31. A method of treating a subject for therapy resistant lung cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor to treat the subject for therapy-resistant lung cancer. 32. The method according to 31, wherein the therapy-resistant lung cancer is characterized by the presence of apoptosis-resistant lung cancer cells. 33. The method according to 32, wherein the method results in one or more of mitochondrial ferrous iron overload, increased ROS generation, excessive lipid peroxidation and PARP activation in the apoptosis-resistant lung carcinoma cells. 34. The method according to any of 31-33, wherein the method comprises inducing parthanatos in lung cancer cells. 35. The method according to any of 31-34, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088. 36. The method according to any of 31-35, wherein the method further comprises administering to the subject a chemotherapeutic agent. 37. The method according to 36, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent. 38. The method according to 37, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof. 39. The method according to any of 31-38, wherein the subject comprises a KRAS / LKB / KEAP1 mutational signature. 40. The method according to 39, wherein the method comprises assaying the subject for the KRAS / LKB / KEAP1 mutational signature. 41. The method according to any of 31-40, wherein the subject is a mammal. 42. The method according to 41, wherein the mammal is a human. Atty. Docket No.: LABIO-006WO 43. The method according to any of 31-42, wherein the lung cancer is non-small cell lung carcinoma (NSCLC). 44. A method of treating a subject for cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor and a chemotherapeutic agent to treat the subject for cancer. 45. The method according to 44, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088. 46. The method according to 44, wherein the N- myristoyltransferase inhibitor is DDD86481. 47. The method according to any of 44-46, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent. 48. The method according to 47, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof. 49. The method according any of 44-46, wherein the chemotherapeutic agent comprises one or more platinum-based compounds. 50. The method according any of 44-46, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound. 51. The method according to any of 44-50, wherein the N-myristoyltransferase inhibitor and a chemotherapeutic agent are administered to the subject simultaneously. 52. The method according to 51, wherein the N-myristoyltransferase inhibitor and chemotherapeutic agent are administered to the subject in a single pharmaceutical composition. 53. The method according to any of 44-50, wherein the N-myristoyltransferase inhibitor and chemotherapeutic agent are administered to the subject sequentially. 54. The method according to any of 44-53, wherein the subject is a mammal. 55. The method according to 54, wherein the mammal is a human. 56. The method according to any of 44-55, wherein the cancer is lung cancer. 57. The method according to 56, wherein the lung cancer is non-small cell lung carcinoma (NSCLC). 58. The method according to any of 44-57, wherein the subject comprises a KRAS / LKB / KEAP1 mutational signature. 59. The method according to 58, wherein the method comprises assaying the subject for the KRAS / LKB / KEAP1 mutational signature. Atty. Docket No.: LABIO-006WO 60. A pharmaceutical composition comprising a synergistically effective amount of a N-myristoyltransferase inhibitor and a chemotherapeutic agent. 61. The pharmaceutical composition according to 60, wherein the N- myristoyltransferase inhibitor is DDD86481. 62. The pharmaceutical composition according to 60 or 61, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent. 63. The pharmaceutical composition according to 62, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof. 64. The pharmaceutical composition according to 60 or 61, wherein the chemotherapeutic agent comprises one or more platinum-based compounds. 65. The pharmaceutical composition according to 60 or 61, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound. 66. A method of treating a subject for lung cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor to treat the subject for lung cancer, wherein the lung cancer is TIM17A dependent. 67. The method of 66, wherein the method comprises, prior to said administering, determining that the lung cancer exhibits TIM17A dependence. 68. The method according to 66 or 67, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088. 69. The method according to 66 or 67, wherein the N- myristoyltransferase inhibitor is DDD86481. 70. The method according to any of 66-69, wherein the subject is a mammal. 71. The method according to 70, wherein the mammal is a human. 72. The method according to any of 66-71, wherein the lung cancer is non-small cell lung carcinoma (NSCLC). 73. A method of killing lung cancer cell, the method comprising: contacting the lunger cancer cell with a N-myristoyltransferase inhibitor to kill the cell, wherein the cell is TIM17A dependent. 74. The method of 73, wherein the method comprises, prior to said contacting, determining that the lung cancer cell exhibits increased TIM17A dependence relative to a control. 75. The method according to 73 or 74, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088. Atty. Docket No.: LABIO-006WO 76. The method according to 73 or 74, wherein the N- myristoyltransferase inhibitor is DDD86481. 77. The method according to any of 73-76, wherein the cell is in vivo and the method comprises administering the N-myristoyltransferase inhibitor to a subject comprising the cell. 78. The method according to any of 73-76, wherein the cell is in vitro. 79. The method according to any of 73-78, wherein the cell is a mammalian cell. 80. The method according to any of 73-78, wherein the cell is a human cell.

[0002] Atty. Docket No.: LABIO-006WO The following is offered by way of illustration and not by way of limitation. EXAMPLES I. The combination treatment of DDD85646 and bortezomib has anti-cancer synergistic effects in vitro. We discovered that DDD85646 is effective against lung cancer cells in vitro and in vivo (Scientific Reports 2020, www(dot)nature(dot)com / articles / s41598-020-68615- w?utm_campaign=related_content&utm_source=CANCER&utm_medium=communities) (Chen et al., Sci Rep 10, 11952 (2020)). Our follow-up unpublished data indicates that DDD85646 causes oxidative stress, which leads to the accumulation of damaged proteins inside cancer cells. Because the proteasome pathway is used by cells to eliminate damaged proteins, we reasoned that combination of DDD85646 with the FDA-approved proteasome inhibitor bortezomib could increase the anti-cancer effects of DDD85646. See FIG.1. To the best of our knowledge the synergistic anti-cancer effect of NMT inhibitors in combination with proteasome inhibitors has not been described. II. Inhibition of myristoylation induces parthanatos through loss of TIM17A and mitochondrial accumulation of ferrous iron. “N-Myristoytransferase Inhibition causes Mitochondrial Iron Overload and Parthanatos in TIM17A-dependent Aggressive Lung Carcinoma.” Abstract Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases. Myristoylation is emerging as a promising cancer therapeutic target, however the molecular determinants of sensitivity to N-myristoyltransferase inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that N-myristoyltransferases are a novel therapeutic target in lung carcinoma cells with LKB1 and / or KEAP1 mutations in a KRAS mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing Atty. Docket No.: LABIO-006WO recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas. Significance Statement KRAS-mutant lung carcinomas with LKB1 and / or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos, thus has the potential to kill apoptosis and ferroptosis resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas. Introduction Myristoylation (protein lipidation with myristic acid) (1) is mediated in human cells by two N-myristoyltransferases (NMT1 and NMT2) (2,3). This lipidation occurs at an N-terminal Glycine within a myristoylation consensus motif, although proximal Lysine residues can also be myristoylated (4,5). Myristoylation regulates protein function by increasing affinity for membranes, promoting calcium / myristoylation switches, facilitating palmitoylation (6), and preventing proteasomal degradation (7). NMT1 is overexpressed in various tumor types (8-12), and has been considered a cancer therapeutic target for years (13). However, few oncoproteins are myristoylated, thus the mechanisms by which NMT1 contributes to cancer progression in most tumors are not well defined. The discovery of highly selective and potent inhibitors of N- myristoyltransferases such as DDD85646, DDD86481, and IMP-1088 (14,15) has enabled mechanistic and preclinical studies in cancer (16-18). Notably, DDD86481 (PCLX-001) is currently in clinical trial for lymphoma and advanced solid malignancies (NCT04836195) (19,20). Lung carcinoma is the leading cause of deaths by cancer, with most cases corresponding to non-small cell lung carcinoma (NSCLC) (21). NSCLCs with KRAS and STK11 (encoding for LKB1) concurrent mutations have extensive metabolic reprogramming (22,23) and are resistant to most treatments, including immunocheckpoint inhibitors (24). KEAP1 mutations Atty. Docket No.: LABIO-006WO are commonly concurrent with KRAS and / or STK11 mutations in NSCLC and confer tolerance to oxidative stress through the KEAP1 / NRF2 pathway, promoting tumor progression and drug resistance (25-27). KRAS, STK11, KEAP1 triple mutant tumors exhibit extensive metabolic reprogramming (26), are highly resistant to chemotherapy, and have poor responses to immunocheckpoint inhibitors (28). Thus, novel therapeutics are urgently needed for this NSCLC subgroup. Mitochondria are central to energy metabolism, redox signaling and metabolic rewiring in tumors (29,30). Notably, mitochondria activity and morphology are influenced by tumor driver mutations, histological subtype, and metabolic demands in vivo (31,32). Most of the mitochondrial proteome is encoded by nuclear DNA, thus the machinery that imports and sorts proteins into mitochondria is key to mitochondria function and health (33). The translocase of outer mitochondrial membrane 20 (TOM20) complex works along with the translocase of inner mitochondria membrane complexes 22 and 23 (TIM22 and TIM23) to transport proteins from the cytoplasm to the mitochondrial compartments (34). Translocase of Inner Mitochondrial Membrane 17 homologues A and B (TIM17A and TIM17B) bind to the TIM23 subunit in the TIM23 complex to form heterodimers (TIM23-TIM17A or TIM23-TIM17B). TIM17A protein expression decreased after activation of the integrated stress response to adapt mitochondria protein import to stress, preventing mitochondria damage and facilitating cell survival (35). On the other hand, elevated TIM17A transcript is associated with worse prognosis in breast cancer (34). It remains unknown whether and how TIM17A contributes to cancer progression. Mitochondria are also essential for the biogenesis of iron-sulfur cluster proteins and heme-containing proteins, which regulate DNA synthesis and repair, protein translation, and participate in the mitochondria electron transport chain (36-38). To fulfill these functions, mitochondria avidly take up and utilize iron (39). Because of its chemical properties, free iron (as opposed to protein-bound iron) generates reactive oxygen species (ROS) (40,41), which may induce oxidative stress if the cell’s antioxidant capacity is overcome. Sustained oxidative stress may cause cell death (42). Parthanatos is one of the cell death mechanisms induced by oxidative stress (43). During parthanatos, excess poly-(ADP)-ribose (PAR) generated by hyperactivated Poly-(ADP)- Ribose Polymerase-1 (PARP1) acts as a death signal that initiates the parthanatos cascade (43). Poly-ADP-ribosylation (PARylation) of Apoptosis Inducing Factor (AIF), causes its nuclear translocation (44,45). PARylated AIF binds to Macrophage Migration Inhibitory Factor (MIF) before both translocate to the nucleus, where MIF cleaves DNA to finalize cell death (46). Parthanatos shares some features with apoptosis, including phosphatidylserine exposure to the Atty. Docket No.: LABIO-006WO external cell surface, DNA fragmentation, and caspase activation (43,44). Parthanatos, however, is independent of caspase activation and dependent on PARP activation, thus it can be rescued with PARP inhibitors. Parthanatos has been mostly studied in the context of neurodegenerative diseases and stroke, where it was first described (43,47). However, recent findings indicate that cancer cells are also susceptible to parthanatos (48,49) , which represents a therapeutic opportunity to kill cancer cells that are resistant to other types of death. MATERIAL AND METHODS Cell Lines HeLa (cat. no. CCL-2 RRID:CVCL_0030), and lung carcinoma lines NCI-H460 (cat. no. HBT-177 RRID:CVCL_0459), NCI-H1792 (cat. no. CRL-5895 RRID:CVCL_1495), NCI-H522 (cat. no. CRL-5810 RRID:CVCL_1567), NCI-H1650 (cat. no. CRL-5883 RRID:CVCL_1483), and NCI-H1437 (cat. no. CRL-872 RRID:CVCL_1472) were obtained from ATCC and maintained at 37 ºC and 5% or 10% CO2 (for DMEM) in a humidified tissue culture incubator. HCC44 cells (cat. no. RRID:CVCL_2060) were from David Shackelford. Hela cells were grown in DMEM (Corning cat. no.10013CV) and lung carcinoma cells in RPMI-1640 (ThermoFisher Scientific cat. no. MT10040CV) both supplemented with 10% Fetal Bovine Serum (Fisher cat. no. MT35015CV). Authentication was performed by with short tandem repeat analysis and cells were regularly tested for mycoplasma infection using MycoAlert mycoplasm detection kit (Lonza cat. no. LT07218). Cells were maintained in culture for a maximum of 6-8 weeks before a new vial was thawed. Tet-system approved FBS was from Clontech (cat. no.631106). General Reagents and Inhibitors NMT inhibitors: DDD85646 was from Aobious (cat. no. AOB6657) or Cayman Chemical (cat. no.13839); PCLX-001 was from Aobious (cat. no. AOB13563) or MCE (cat. no. HY- 147308) and IMP-1088 was from Cayman Chemical (cat. no.25366). Deferoxamine (cat. no. 14595), Ferrostatin-1 (cat. no.17729) Liproxstatin-1 (cat. no.17730), Erastin (cat. no.17754), Trolox (cat. no.10011659), Necrostatin-1 (cat. no.11658), iFSP1 (cat. no.29483), Olaparib (cat. no.10621), Z-VA-DL-D(OMe)-FMK (cat. no.27421), Disulfiram (cat. no.15303), Deferoxamine (cat. no.14597), Staurosporine (cat. no.81590), 4-Hydroxynonenal (cat. no. 32100), Cisplatin (cat. no.13199) and Pemetrexed (cat. no.14269) were from Cayman Chemical. Ferric Citrate (cat. no. F3388-250G) was from Sigma-Aldrich, Crystal Violet (cat. no. C581-25) was from Fisher, Propidium Iodide (cat. no.556463) was from BD Pharmingen; Hanks Atty. Docket No.: LABIO-006WO Balanced Salt Solution (HBSS) was from ThermoScientific (cat. no. J67763.K2). Puromycin was from InVivoGen (cat. no. ANTPR1), and Doxycycline was from MCE (cat. no. HY-N0565B). Primary antibodies Antibodies against NMT1 (cat. no.11546-1-AP, RRID:AB_2153157), TOM20 (cat. no. 11802-1-AP, RRID:AB_2207530), TOM40 (cat. no.18409-1-AP, RRID:AB_2303725), SAM50 (cat. no.28679-1-AP, RRID:AB_2881192), TIM17A (cat. no.11189-1-AP, RRID:AB_2271661), TIM17B (cat. no.11062-1-AP, RRID:AB_2201995), β-Tubulin (cat. no.66240-1-Ig, RRID:AB_2881629), NDUFAF4 (cat. no.26003-1-AP, RRID:AB_2880329) and FSP1 / AIFM2 (cat. no.20886-1-AP, RRID:AB_2878756) were from ProteinTech. Antibodies against Poly / Mono-ADP Ribose (cat. no.83732, RRID:AB_2749858), AIF (cat. no.5318, RRID:AB_10634755), MIF (cat. no.75038, RRID:AB_3101808), β-Actin (cat. no.8457, RRID:AB_1095048), Lamin A / C (cat. no.4777, RRID:AB_10545756), phospho-H2A.X (cat. no. 9718, RRID:AB_2118009) and GAPDH (cat. no.5174, RRID:AB_10622025) were from Cell Signaling Technology. HSP60 antibody (cat. no. MAB1800, RRID:AB_2118930) was from R&D Systems. RNA interference siRNA against human NMT1 corresponds to oligo 3026786108-000020 from Sigma; TIM17A SMARTpool siRNA (M-012739-02) was from Dharmacon. siRNA oligos #1 and #2 targeting human TIM17A correspond to oligo D-012739-02 (Dharmacon) and oligo 3031277378 (Sigma) respectively. NDUFAF4 SMARTpool siRNA (M-020684-01) and control non-targeting individual oligos or pools were from Dharmacon. siRNAs were transfected using Opti-MEM (Gibco 31985062) and Lipofectamine RNAimax (13778500, ThermoFisher Scientific), and cells processed at 72 hours after transfection. pLKO-Tet-puro lentiviral constructs were used to clone the following shRNAs: NMT1 #10 (TRCN0000035710), NMT1 # 68 (TRCN0000289868) and TIM17A (TRCN0000275956). Constructs and lentivector stocks, including pLKO Tet-puro non targeting control were prepared by the Viral Vectors Shared Resource at Sanford-Burnham Prebys Medical Research Institute (La Jolla). Infected cells were selected with puromycin (2.5 µg / ml for H460, 1 µg / ml for H1792 and H1437 and 1.5 µg / ml for H522). To induce shRNA expression, doxycycline was used at 500 ng / ml for 72 hours. Western Blotting Atty. Docket No.: LABIO-006WO Proteins were extracted with RIPA lysis buffer containing fresh protease and phosphatase inhibitors. Cytoplasmic and nuclear fractions were separated with NE-PER kit (ThermoFisher Scientific, cat. no.78835). Total protein content was estimated using BCA assay (cat. no.23225 Pierce). Western blotting was performed using standard protocols. Briefly, membrane was blocked for 1 hour at RT in 5% milk (BioRad) and incubated overnight at 4°C. After washing in PBS containing 0.1 % Tween 20, membranes were incubated with horseradish peroxidase-conjugated anti-mouse or anti-rabbit IgG (GE Healthcare). Images were acquired in a BioRad ChemiDoc MP Imaging System using Supersignal WestPico PLUS (cat. no.34580, Pierce). ImageJ software v1.52p (RRID:SCR_003070) was used for quantification of digital images and Excel software for normalizing to protein loading control. Immunofluorescence Cells were grown on glass coverslips and fixed in 4% paraformaldehyde (Electron Microscopy Sciences) for 15 minutes. For MIF staining, cells were subsequently fixed for 5 minutes in ice-cold methanol. Cells were blocked and permeabilized for 1 hour using PBS containing 0.1% Triton X100 and 3% Bovine Serum Albumin fraction V (BSA) from Fisher. Primary antibody was diluted in PBS containing 0.1% Triton X100 and 0.3% BSA and incubated overnight at 4°C. After washing, cells were incubated with anti-rabbit or anti-mouse IgG conjugated with AlexaFluor-488 or AlexaFluor-594 (ThermoFisher Scientific) (1:500) for 1 hour. Coverslips were mounted in Vectashield medium containing DAPI (cat. no. H1200-10, Vector Labs). Immunofluorescence images were acquired using a fluorescence AxioImager Zeiss microscope provided with a Zeiss AxioCam 503 camera and ZEISS Zen Microscopy Software (RRID:SCR_013672). Images were exported as “TIF” and quantified using ImageJ 1.52p, or ZEISS Zen Microscopy Software. Adobe Photoshop (RRID:SCR_014199) was used to separate individual channels and / or crop digital images. Immunohistochemistry Excised H460 tumors were fixed in formalin, dehydrated and embedded in Paraplast Plus (Sigma, cat. no. P3683). Sections (0.3 µm) were prepared and processed for IHC using standard protocols. Briefly, sections were deparaffinized and rehydrated in distilled water. Heat- induced antigen retrieval was performed for 1 minute in a pressure cooker in citrate-based antigen-unmasking solution (Vector, cat. no. H3300). After cooling down, sections were blocked for 10 minutes in Bloxall endogenous blocking solution (Vector, cat. no. SP-6000) and 20 minutes with normal goat serum (Vector, cat. no. S-1012). Primary antibodies against p-H2A.X Atty. Docket No.: LABIO-006WO and AIF were diluted in 1% BSA-containing Tris buffer saline (TBS) at 1:200 and incubated overnight at 4°C. After washing, samples were incubated with goat-anti-rabbit IgG biotinylated antibody (Vector, cat. no. BA-1000), Vectastain Elite ABC reagent (Vector, cat. no. PK-6100) and DAB (Vector, cat. no. SK-4100). Samples were dehydrated and mounted in Permount (Fisher, cat. no. SP-15). Images were taken on an ECHO Revolve microscope, exported as TIFF and cropped using Adobe Photoshop. Iron Measurement Total iron content. Cells growing in 15 cm diameter dishes treated with vehicle or NMT inhibitor were collected using 0.5% Trypsin EDTA-free (Hyclone, cat. no. SV3003701) and an aliquot reserved for cell counting. After low-speed centrifugation, cell pellets were weighted and immediately frozen. Inductively coupled plasma mass spectrometry (ICP-MS, NexION 2000, PerkinElmer) analysis was performed to detect iron in cell pellets. Each sample was transferred to clean teflon vessels for acid digestion. Digestion was carried out with concentrated HNO3(65- 70%, Trace Metal Grade, Fisher Scientific) with a supplement of H2O2(30%, Certified ACS, Fisher Scientific) at 190 °C for 20 minutes in a microwave digestion system (Titan MPS, PerkinElmer). Once the sample was cooled to room temperature, it was subsequently diluted to make a final volume of 10 ml by adding filtered deionized water for analysis. The calibration curve was established using a standard solution while the dwell time was 50 milliseconds with thirty sweeps and three replicates with background correction. Iron content (ng / mg) was normalized to total cell number for each sample and represented as iron content per million cells. Ferric Iron content. Cells treated with vehicle or NMT inhibitor were grown on glass coverslips and fixed in 10% neutral buffered formalin. Cells were subsequently washed with PBS and stained with Prussian blue (Polysciences, cat. no.24199) following vendor’s recommendation. Signal was amplified using Vector’s SG Substrate Kit (Vector Laboratories, cat. no. SK-4700) following the kit’s technical datasheet. Images were acquired using an Olympus IX83 microscope and bright field imaging. Iron deposits were quantified as percent area covered using ImageJ and data normalized to cell number. Cytoplasmic Ferrous Iron content. Cells growing on glass-bottom black 96-well plates (Agilent) were assayed for cytoplasmic ferrous iron content using FerroOrange (Dojindo, cat. no. F374) following the manufacturer’s protocol. Fluorescence at 560 nm was measured using a Atty. Docket No.: LABIO-006WO BioTek Synergy H1M plate reader. A duplicated 96-well plate containing cells treated in parallel was stained with 0.4% crystal violet in 30% Methanol for 30 minutes at room temperature. After washing, staining was extracted from dried plates with a 10% SDS solution and absorbance measured at 570 nm using a BioTek plate reader. Data from FerroOrange fluorescent intensity was normalized to crystal violet absorbance values for each experiment. Mitochondrial Ferrous Iron content. Cells were grown on glass coverslips and treated with vehicle or NMT inhibitor for the indicated periods of time. Cells were washed twice with HBSS and treated with Mito-FerroGreen (Dojindo, cat. no. M489) working solution following the technical manual. Fluorescence images were taken randomly using a Zeiss AxioImager microscope provided with a Zeiss AxioCam 503 camera and ZEISS Zen Microscopy Software. Images were exported as “Tiff”. ImageJ was used to quantify determine the area covered by the green signal on each picture. After normalizing to the number of cells for each image in Excel, data were analyzed with GraphPad Prism 10 (RRID:SCR_002798). ROS Measurement Cells were grown on glass coverslips and treated with vehicle or NMT inhibitor for the indicated periods of time. After removing media, cells were washed twice with HBSS and treated with Highly Sensitive DCFH-DA (Dojindo, cat. no. R252) at 1:2,000 in HBSS for 30 minutes following the technical manual. Fluorescence images were acquired randomly using a Zeiss AxioImager microscope provided with a Zeiss AxioCam 503 camera and ZEISS Zen Microscopy Software. Images were exported as “Tiff”. ImageJ was used to quantify the area covered by the green signal on each picture. After normalizing to the number of cells for each image in Excel, data were analyzed with GraphPad Prism 10. Colony forming assay. Cells (~500-1,000 per well) were plated in 6-well plates and treated 24 hours after plating with the indicated amount of inhibitors or with Doxycycline. After 6-10 days in culture, cells were stained with 0.1% crystal violet in 30% MeOH for 30 minutes, washed and let dry. ImageJ was used to quantify colony number or % area covered on digital images. IC50calculation Atty. Docket No.: LABIO-006WO Cells were seeded in 384-well white plates (Greiner) at 375 to 1,500 cells per well according to the linear relationship measured from a standard curve of each cell line.24 hours after seeding, cells were treated with NMT inhibitor (three-fold dilution, eight dilution points, in duplicate). After 72 hours of treatment, cell viability was measured using CellTiter Glo Luminescent Cell Viability Assay (Promega), according to the manufacturer’s description, and IC50values were calculated using the percentage of growth of treated cells versus the DMSO control with GraphPad Prism 10 software. CCK8 viability test Cells growing in 96-well plates were treated with vehicle or NMT inhibitor or co-treated with additional inhibitors for the indicated periods of time. Cell Counting Kit-8 (Dojindo cat. no. CK04) was incubated for 1-3 hours at 37°C and absorbance measured at 450 nm using a BioTek Synergy H1M. Values were analyzed with Excel and Prism 10. Cell death Detection Annexin / PI staining Treated cells were analyzed using FITC Annexin V Apoptosis Detection Kit I, (BD cat. no.556547). Briefly, after compound treatment, floating cells were collected and combined with adherent cells that were harvested using Accutase (BioLegend, cat. no.423201). Cells were washed with cold PBS and re-suspended at 1 x 106cells / ml in the provided binding buffer. Cells (1 x 105total) were incubated for 15 minutes in the dark with 1 μl of FITC Annexin V and 5 μl PI. After staining, 400 μl of binding buffer was added to each tube prior to analysis using a BD LSRII cell analyzer (BD Biosciences). Single stains for Annexin V and PI of untreated cells were used for compensation. The distribution of cell populations was performed using FlowJo (RRID:SCR_008520) 10.6.2 software (BD Biosciences). Propidium Iodide staining Floating cells were collected and combined with adherent cells that were harvested using TrypLE Express Enzyme reagent (Gibco, cat. no.126050), Cells were washed with PBS and re-suspended in 1 ml of PBS-EDTA at a cell concentration of 1 x 106cells / ml. PI (5 μl) was added to each sample and incubated for 15 minutes at room temperature in the dark. Samples were analyzed using a BD LSRII cell analyzer (BD Biosciences). Samples were compensated to unstained cells treated as above. The distribution of dead and alive cell populations was calculated using FlowJo 10.6.2 software (BD Biosciences). Atty. Docket No.: LABIO-006WO Dead / live imaging kit Cultured cells were washed with HBSS and stained with Live / Dead Cell imaging kit (ThermoFisher, cat. no. R37601) dissolved in HBSS following the technical manual. An ECHO Revolve microscope was used to acquire images. ImageJ was used to manually score the number of green and red cells on each image. Data were analyzed in Excel and GraphPad Prism 10. Cell cycle analysis After compound treatment, floating cells were collected and combined with adherent cells that were harvested with Accutase (BioLegend, cat. no.423201). Cells were fixed in 70% ethanol overnight at -20°C. Fixed cells were washed two times with PBS and pellets resuspended in 0.5 ml of Propidium Iodide (PI) staining buffer (BD Biosciences, cat. no. 550825) at a concentration of 2 × 106cells / ml and incubated at room temperature for 30 minutes in the dark prior analysis. Fluorescence intensity was measured using a BD LSRII cell analyzer (BD Biosciences). For each sample, at least 1 × 105events were recorded. Collected events were analyzed using FlowJo 10.6.2 software (BD Biosciences) to determine cell cycle distribution. Lipid Peroxidation Detection Treated cells were incubated with 5 µM of Bodipy 581 / 591 C11 (ThermoFisher, cat. no. D3861) in complete medium for 30 minutes at 37 ºC. Cells were collected using TrypLE Express Enzyme reagent (Gibco cat. no.126050), washed and re-suspended in ice cold PBS. Data acquisition and analysis were performed in a BD FACSyphony A5 flow cytometer (BD Biosciences) using BD FACSDiva Software (RRID:SCR_001456) v9.0. The median fluorescence intensity for the green channel of each sample was determined and normalized to DMSO treated control cells using FlowJo v10.8.1 software (BD Biosciences). Electron Microscopy Cells growing in tissue culture plates were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer pH 7.4 for one hour on ice. Cells were scraped and pelleted. After washing with 0.1 M cacodylate buffer, pellets were postfixed in 1% OsO4 in 0.1 M cacodylate buffer for 1 hour on ice, stained with 2% uranyl acetate for 1 hour on ice, and dehydrated in graded series of ethanol (50-100%) while remaining on ice. The cells were then subjected to Atty. Docket No.: LABIO-006WO one wash with 100% ethanol and two washes with acetone (10 minute each) and embedded with Durcupan. Sections were cut at 60 nm on a Leica UCT ultramicrotome and picked up on 300 mesh copper grids. Sections were post-stained with 2% uranyl acetate for 5 minutes and Sato’s lead stain for one minute. The images were acquired with a Tecnai G2 Spirit BioTWIN operated at 80 KeV and equipped with an FEI eagle 4k x 4k camera. Xenograft mouse model All animal work was performed in strict accordance with an animal usage protocol approved by the University of California Los Angeles Animal Care and Use Committee (IACUC# ARC-2012-094). NSG female mice RRID:IMSR_JAX:005557 (Jackson Laboratories) of ~8 weeks of age were injected subcutaneously in one flank with a suspension of saline and ~30% Matrigel (Corning cat. no.356231) containing 1x106H460 cells. Around two weeks after injection, animals were distributed into three experimental groups with an average tumor volume of ~ 140 mm3each and dosed with vehicle (12.5% DMSO in saline) or PCLX-001 via daily subcutaneous injection in the scruff of the neck (we found that intraperitoneal injection was not tolerated). Control group contained 9 animals, and each of the experimental groups contained 10. Consistent with a previous report (18), mice receiving PCLX-001 suffered dehydration and weight loss. Body weight was monitored daily and treatment of mice in the 50 mg / kg group was discontinued after 10 days due to sustained weight loss. From day 10 to endpoint (day 18) animals in the 50 mg / kg group were only injected subcutaneously with 200 μl of lactated Ringer’s solution. Tumor volume was estimated using the formula V = 0.5 × L × W2, where L is the tumor length (highest dimension) and W is the tumor width. Mass Spectrometry based proteomics H1792 cells treated with DMSO control or 1 μM DDD85646 for 48 hours (n=3 biological replicates) were lysed in 8M urea, 100mM Tris-Cl, pH 8.0. Equal amount of protein (estimated using BCA assay cat. no.23225 from Pierce) for each sample was reduced and alkylated by the sequential addition of 5 mM tris (2-carboxyethyl) phosphine and 10 mM iodoacetamide. This was followed by treatment with single-pot, solid-phase-enhanced sample preparation (SP3) protocol for protein clean-up (50). Following SP3, eluates were proteolytically digested with Lys- C and trypsin at 37°C overnight. Peptides were subjected to offline SP3-based peptide clean-up and subsequently analyzed by LC-MS / MS. Briefly, peptides were separated by reversed phase chromatography using 75 μm inner diameter fritted fused silica capillary column packed in- house to a length of 25 cm with bulk 1.9mM ReproSil-Pur beads with 120 Å pores. The Atty. Docket No.: LABIO-006WO increasing gradient of acetonitrile was delivered by a Dionex Ultimate 3000 (ThermoFisher Scientific) at a flow rate of 200nL / min. The MS / MS spectra were collected using data dependent acquisition on Orbitrap Fusion Lumos Tribrid mass spectrometer (ThermoFisher Scientific) with an MS1 resolution (r) of 120,000 followed by sequential MS2 scans at a resolution (r) of 15,000. The data generated by LC-MS / MS were analyzed on MaxQuant (RRID:SCR_014485) bioinformatic pipeline (51). The Andromeda integrated in MaxQuant was employed as the peptide search engine and the data were searched against Homo sapiens (Uniprot Reference UP000005640). Briefly, a maximum of two missed cleavages was allowed. The maximum false discovery rate for peptide and protein was specified as 0.01. Label-free quantification (LFQ) was enabled with LFQ minimum ratio count of 1. The parent and peptide ion search tolerances were set as 20 and 4.5 ppm respectively. The MaxQuant output files were subsequently processed for statistical analysis of differentially enriched proteins using Analytical R tools for mass spectrometry (artMS) (52). Briefly, the MSstats function of artMS was used for relative quantification and global median normalization of protein intensities. Prior to statistical analysis, missing protein abundance values were imputed based on the lowest value of protein abundance detected in that sample under the assumption that failure to detect a protein in a sample was due to its low abundance. Log2 fold changes were calculated for indicated comparisons. Significance testing for differential expression was determined using a moderated t-test from the LIMMA (RRID:SCR_010943) package and FDR adjustment by the Benjamini- Hochberg method with probability of a false-positive discovery cut-off of 0.05. Data Mining Publicly available gene expression data from The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) was queried from BioPortal (RRID:SCR_002713)(53) (specifically TCGA-LUAD Pan Cancer Atlas, n=501, n=event=181). Patient information such as age and overall survival status and months were also provided. For gene expression values, the RSEM batch normalized count data was used (from Illumina HiSeq_RNASeqV2). Differential gene expression analysis for TCGA data was also performed using BioPortal. The lung carcinoma IC50(half-maximal inhibitory concentration) for the NMT inhibitor ICL1100013 (DDD85646) were queried from Genomics of Drug Sensitivity in Cancer (RRID:SCR_011956) v8.4 July 2022. KRAS, EGFR, TP53, STK11 and KEAP1 mutation status for lung adenocarcinoma cell lines were queried from Cancer Dependency Map Portal (RRID:SCR_017655). Comparison among the three groups KRAS, STK11 and KEAP1 log2 transformed was performed by Anova assuming equal variance. Atty. Docket No.: LABIO-006WO Pathway analysis by gene over-representation was performed using Fisher’s Exact Test against the WikiPathways (RRID:SCR_002134) database as well as Gene Ontology (RRID:SCR_002811) biological processes and cellular components. A list for upregulated and downregulated genes was inputted separately for over-representation analysis on WebGestalt: WEB-based GEne SeT AnaLysis Toolkit (RRID:SCR_006786). Benjamini-Hochberg procedure was applied to correct the false discovery rate associated with multiple hypothesis testing. The subset of proteins specific to the mitochondria was queried using the Human Protein Atlas HPA (RRID:SCR_006710). According to this database, 6% (1119 proteins) of all human proteins have been experimentally detected in the mitochondria of which 539 were detected in our dataset. Moderated t-statistics from the entire proteomic data array was used. TIM17A dependency in lung adenocarcinoma cell lines was queried from Cancer Dependency Map Portal (DepMap-23Q2). TIM17A dependency was estimated using the CRISPR DepMap Scores with the Chronos algorithm. Association between NMTi sensitivity (IC50) and TIM17A dependency (CRISPR DepMap Scores) was tested using Spearman’s rank correlation. Statistical Analysis Comparison of survival estimates between two groups was performed using a log-rank test and plotted using Kaplan-Meier curves with shaded bands for 95% confidence intervals. Overall survival was defined as the interval from initial diagnosis to patient death or last follow- up (censored at 8 years). Comparison of means between two groups was performed using two-sided Student’s t- test with an alpha threshold of 0.05 for statistical significance. Excel, GraphPad Prism 10, and R Project for Statistical Computing (RRID:SCR_001905) softwares were used for statistical analysis and plotting graphs. For testing whether two continuous variables are significantly correlated, the non-parametric Spearman’s rank test was used. Additional Software Diagrams in Figs.4, 6 and 8 were created with Biorender (RRID:SCR_018361). Data availability. Materials and data generated during the current study are available from the corresponding author on reasonable request. Results Atty. Docket No.: LABIO-006WO N-myristoyltransferase-1 is a novel therapeutic target in aggressive and therapy- resistant lung carcinoma. Pharmacological inhibition of NMTs is emerging as a promising therapeutic strategy in lymphoma (18,20), but its therapeutic potential in lung carcinoma, the cancer causing the highest number of annual deaths, has not been fully explored. We used The Cancer Genome Atlas (TCGA) to explore the relationship between NMT transcript expression and patient outcome and found that high NMT1 (but not NMT2) transcript correlated with poor outcome in lung adenocarcinoma (FIG.10A). We previously showed that H460 and H1792 K-RAS mutant lung carcinoma cells are sensitive to the NMT inhibitor (NMTi) DDD85646 (16). We calculated the half inhibitory concentration (IC50) of DDD85646 on EGFR mutant (H1975, H1650) and KRAS / EGFR wild-type lung carcinoma cells (H1299, H522) at 72 hours of treatment. This revealed heterogeneous responses to NMTi treatment (FIG.10B). To expand this analysis, we used Genomics of Drug Sensitivity in Cancer, where DDD85646 is deposited as ICL1100013 (54). A total of 58 NSCLC lines were manually annotated for their driver mutation status based on the Cancer Dependency Map portal. Our search for associations between NMTi sensitivity and driver mutations revealed that cells with triple mutation in KRAS, LKB1, and KEAP1 (n=9) were more sensitive (P=0.008) to NMT inhibition than those lacking any of these mutations (n=25) or than those containing KRAS mutation alone (n=11, P= 0.005) (FIG.2A). The number of double mutant KRAS / LKB1 or KRAS / KEAP1 was not sufficiently large to perform statistical analysis. Our data suggest that NMT1 is a potential therapeutic target in lung carcinomas with mutant KRAS and LKB1 and / or KEAP1 (KL / K)MUT(also referred to herein as “(KL / K)MUT”; likewise, the wild type version for comparison is referred to herein as “(KL / K)WT” and also as “(KL / K)WT”), which are highly aggressive and resistant to current therapies, including immune checkpoint inhibitors (28). We selected three (KL / K)MUTand three (KL / K)WTlung carcinoma cell lines for further study: The first group included HCC44 and H460 (KRAS / LKB1 / KEAP1 triple mutant) along with H1792 (KRAS / KEAP1 double mutant). The second group included H522 and H1650 (KRAS / LKB1 / KEAP1 wild-type), along with H1437 (KRAS and KEAP1 wild-type, LKB1 mutant). In addition to DDD85646, other NMT inhibitors have been characterized for their sensitivity and specificity, including the derivative PCLX-001 (18), and the structurally unrelated IMP-1088 (15) (FIG.10C). The viability of the selected cell lines after a dose-response of PCLX-001 for 72 hours (FIG.2B) was comparable to the sensitivity to DDD85646 deposited in Genomics of Drug Sensitivity in Cancer. (KL / K)MUTcells were sensitive (EC50below 0.2 μM) whereas (KL / K)WTcells were relatively resistant (EC50values over 1 μM) (FIG.2B). The responses to DDD85646 and Atty. Docket No.: LABIO-006WO IMP-1088 were comparable to PCLX-001 (FIG.10D,E). NMT1 immunoblotting, however, revealed no differences in NMT1 protein expression between the six cell lines (FIG.2C). To demonstrate that the effects of NMTi on cell viability were on target, we generated H460, H1792, H522 and H1437 cells stably expressing a Tet-inducible shRNA targeting NMT1 and use them to compare cell viability upon Doxycycline treatment for 72 hours. Doxycycline did not affect the viability of cells expressing non-targeting shRNA control (FIG.10F). Whereas the viability of H460 and H1792 (KL / K)MUTdecreased by 60% and 40% respectively, the viability of H522 and H1437 (KL / K)WTwas not altered by Doxycycline treatment despite a comparable level of NMT1 knock-down (FIG.2D). Using Tet-inducible H460 cells expressing two different NMT1 shRNAs, we confirmed that colony formation ability was dependent on the degree of NMT1 silencing (FIG.10G). H1792 and HCC44 cell lines expressing inducible NMT1 shRNA also showed decreased colony forming ability upon Doxycycline treatment (FIG.11 A,B). Notably, the NMT inhibitor PCLX-001 efficiently reduced tumor growth in H460 xenografts at dosages of 25 and 50 mg / Kg daily (FIG.2E and FIG.11C). Animals in the 50 mg / kg group experienced dehydration and weight loss (FIG.11D), thus were only treated for 10 days. Despite treatment discontinuation, the anti-tumor effect of PCLX-001 was maintained until the end of the study (FIG.2D). Taken together, our data indicate that NMT1 is a novel therapeutic target in (KL / K)MUTlung carcinoma, an aggressive and therapy-resistant lung cancer subtype. N-myristoyltransferase inhibition alters transferrin receptor trafficking and decreases cytoplasmic ferrous iron content. KRAS is not myristoylated and NMT1 protein expression levels were comparable between sensitive and resistant cells (FIG.2C). Thus, the molecular determinants of the sensitivity of (KL / K)MUTcells to NMTi treatment were unclear. We performed mass spectrometry-based proteomics analysis (LC-MS / MS) on (KL / K)MUTH1792 lung carcinoma cells treated with 1 μM DDD85646 or vehicle control for 48 hours, when cells are still viable (16). Over-representation analysis of proteins upregulated with NMTi treatment (765 / 4,929 uniprot IDs, P <0.05) by Fisher’s Exact Test (P-adjusted < 0.05) against Gene Ontology biological processes revealed enrichment of secretory and vesicle transport- related processes in drug-treated cells (FIG.12A), a finding consistent with a previous study on HeLa cells (17). Using transferrin receptor 1 (TfR1) staining as a surrogate for vesicle trafficking within the endocytic recycling pathway, we found that NMTi caused accumulation of TfR1 at the Atty. Docket No.: LABIO-006WO plasma membrane and intracellular clusters, but staining was absent from intracytoplasmic vesicles (FIG.3A). This effect was not a consequence of cell death because normal distribution of TfR1 was almost recovered ~24 hours after drug removal even in cells treated for 72 hours (FIG.12B). TfR1 is the main mechanism for cellular uptake of iron, an essential metal that is necessary for DNA replication (55). Disrupted TfR1 trafficking could decrease cellular iron availability, halt DNA replication, and decrease cell viability. However, ferric citrate (a TfR1- independent cell permeable form of iron) did not increase the colony forming ability of cells treated with DDD85646 (Suppl. FIG.12C), indicating that NMT inhibition is unlikely to cause global iron deficiency. In agreement, measurement of total iron content using inductively coupled plasma mass spectrometry (ICP-MS) in H460 cells showed no differences between control and NMTi treatment at 24, 48 or 72 hours (Fig S3D). This was largely consistent with our analysis of ferric iron content using enhanced Perls’ Prussian Blue staining in H1792 cells treated with DDD85646 (FIG.12E). We concluded that NMTi treatment does not decrease total iron availability in NMTi-sensitive lung carcinoma cells despite altered TfR1 subcellular distribution. The cellular levels of iron are strictly regulated to avoid deficiency while preventing toxicity resulting from iron-dependent generation of reactive oxygen species (ROS). Accumulation of TfR1 at the plasma membrane (FIG.3A and FIG.12B) is a marker of ferroptosis (56), a ferrous iron-mediated cell death mechanism characterized by excessive lipid peroxidation. To investigate whether NMTi treatment could cause ferroptosis, we first measured cytoplasmic ferrous iron content using FerroOrange. Surprisingly, cytoplasmic ferrous iron levels were decreased at 48 and 72 hours of treatment with NMTi in H460 and H1792 cells (FIG.3B and FIG.13A). Taken together, our data indicates that NMT inhibition alters ferrous iron homeostasis without decreasing total cellular iron content. N-myristoyltransferase inhibition causes mitochondrial ferrous iron overload, elevated ROS, and excessive lipid peroxidation in sensitive lung carcinoma cells. We reasoned that decreased cytoplasmic ferrous iron content in drug-treated cells could occur at the expense of ferrous iron accumulation in a different subcellular compartment. Using Mito-FerroGreen, we observed that NMTi caused mitochondrial ferrous iron accumulation at 24 hours of treatment in sensitive (KL / K)MUTcells (FIG.3C and FIG.13B). In contrast, none or little ferrous iron accumulated in the mitochondria of resistant (KL / K)WTcells (FIG.3D and FIG.13B). Atty. Docket No.: LABIO-006WO Transfection of NMT1 siRNA into HeLa cells (which are sensitive to NMTi (16,17)) also led to mitochondrial ferrous iron overload (FIG.13C). Because free ferrous iron is a known source of reactive oxygen species (ROS), we evaluated ROS generation after NMTi treatment using DCFH-DA. As expected, NMTi treatment of (KL / K)MUTcells led to a sustained increase in ROS from 24 to 72 hours of treatment whereas a modest no increase was seen in (KL / K)WTcells (Fig 2D and FIG.13D). Excessive ROS, which crosses cellular membranes causes widespread lipid peroxidation, a known consequence of oxidative stress that is associated with ferroptosis. Using the lipid peroxidation sensor Bodipy 581 / 591 C11 and flow cytometry we confirmed that NMTi increased lipid peroxidation in a dose and time-dependent manner in (KL / K)MUTH460 cells (FIG.14A,B). The NMT inhibitors PCLX- 001 and IMP-1088 had a similar effect (FIG.14C). Next, we wonder whether the extent of lipid peroxidation correlated with sensitivity to NMTi. DDD85646 treatment (2 μM for 96 hours) led to increased lipid peroxidation in NMTi sensitive but not in resistant cells (FIG.4A). Thus, lipid peroxidation in sensitive cells was likely caused by excessive ROS generated due to mitochondrial ferrous iron accumulation. Consistent with that possibility, both the iron chelator Deferoxamine and the antioxidant Trolox attenuated lipid peroxidation in sensitive H460 cells treated with DDD85646 (FIG.14 D,E). NMTi and genetic targeting of NMT1 also increased lipid peroxidation in HeLa cells (FIG.14F,G). Ferroptosis Suppressor Protein-1 (FSP1) is a myristoylated protein that protects from lipid peroxidation and ferroptosis (57,58) . Our proteomic analysis revealed decreased abundance of FSP1 after NMTi treatment, which we verified by immunoblotting (FIG.14H). However, while inhibition of FSP1 with the small compound iFSP1 (57) sensitized H460 cells to NMTi, it did not cause significance cell death as a single agent (FIG.14I). Thus, loss of FSP1 is unlikely to explain the sensitivity of lung carcinoma cells to NMTi treatment. Taken together, our findings indicate that NMT inhibition in sensitive (KL / K)MUTlung carcinoma cells cause mitochondrial ferrous iron overload, which leads to excessive ROS generation and lipid peroxidation. Inhibition of N-myristoyltransferase causes parthanatos in (KL / K)MUTlung carcinoma cells. We previously showed that NMTi decreases cell proliferation in sensitive H1792 and H460 cells (16). Using flow cytometry and cell cycle analysis, we now confirmed that NMTi prevents cell cycle progression, leading to accumulation of cells in G1 (FIG.15A). We had also reported that H1792 cells die after ~72 hours of NMTi treatment (16). To investigate the Atty. Docket No.: LABIO-006WO mechanism by which sensitive lung cancer cells die in response to NMTi, we performed Annexin-V / PI staining of H460 cells treated with 2 μM of DDD85646 for 96 hours (FIG.15B). NMTi increased the amount Annexin-V and Annexin-V / PI double-positive cells (considered as early and late apoptotic respectively). There was also a modest increase in cells with high PI and low Annexin-V staining (considered as non-apoptotic death). Although this analysis indicated death by apoptosis, co-treatment of H460 cells with the pan-caspase inhibitor Z-VAD- FMK failed to prevent death induced by NMTi (FIG.4B) despite preventing apoptosis of H460 cells treated with 0.2 μM Staurosporine for 24 hours (FIG.15C). The above finding indicates that sensitive lung carcinoma cells die by a caspase-independent mechanism in response to NMTi. Despite the phenotypic similarities of NMTi-induced death with caspase-independent types of death such as ferroptosis (accumulation of TfR1 at the plasma membrane and excessive lipid peroxidation) or pyroptosis (excessive lipid peroxidation), death of H460 cells treated with DDD85646 was not rescued by inhibitors of ferroptosis (Liproxstatin-1, FIG.4C and FIG.16A) or pyroptosis (Disulfiram, FIG.16B). Inhibitors of necroptosis (Necrostatin-1) also failed to rescue lung carcinoma cells from NMTi-induced cell death (FIG.16C). To gain insights into the elusive mechanism by which (KL / K)MUTlung carcinoma cells die in response to NMTi, we used transmission electron microscopy to analyze the ultrastructure of H1792 cells treated with 1 μM DDD85646 for 24 and 72 hours. Notably, cells treated for 72 hours showed a striking electron-dense cytoplasm previously described in dark microglia cells as the result of extensive oxidative damage (59) (FIG.5A). Parthanatos is a type of apoptosis- independent programmed cell death characterized by extensive oxidative stress (43). During parthanatos, PARP) is hyperactivated and causes extensive mono- or poly-ADP ribosylation (PAR) of proteins, including apoptosis inducing factor (AIF), which then translocates from mitochondria to the nuclei along with macrophage-inducing factor (MIF) (60), causing fragmentation of DNA into large fragments and cell death (see diagram in FIG.5B). We had noticed that the nuclei of dying cells contained large DNA fragments (FIG.17A), thus we investigated whether NMTi causes parthanatos in (KL / K)MUTlung carcinoma cells. Immunoblotting with an anti-PAR antibody revealed increased PARylated proteins in NMTi treated lung carcinoma cells (FIG.5C). In addition, sensitive H460 but not resistant H522 cells expressing a Tet-inducible NMT1 shRNA had increased PARylation in the presence of Doxycycline (FIG.5D). Immunofluorescence revealed the accumulation of nuclear MIF in H460 and H1792 cells treated with NMTi (FIG.5E and FIG.17B), and immunoblotting revealed that AIF was enriched in the nuclear fraction of NMTi-treated, but not control cells (FIG.5F). Notably, Atty. Docket No.: LABIO-006WO AIF was largely cytoplasmic in control H460 xenografts, but mostly nuclear in H460 xenografts from mice treated with PCLX-001 (FIG.5G and FIG.17D). To confirm the role of PARP in death induced by NMTi, we used the PARP inhibitor Olaparib, a parthanatos inhibitor (61). Treatment of H460 cells with Olaparib in the presence of NMTi effectively prevented PARylation (FIG.17C). Notably, despite causing cell death on its own, Olaparib decreased NMTi-induced cell death at 72 and 96 hours of treatment (FIG.5H and FIG.18A-C). Taken together, our data indicate that NMT inhibitors are a new class of parthanatos- inducing drugs with the potential to kill cancer cells that are resistant to other forms of death such as apoptosis or ferroptosis. Furthermore, our findings also indicate that parthanatos may occur downstream mitochondrial ferrous iron accumulation and that cells undergoing parthanatos may display features associated with ferroptosis, such as excessive lipid peroxidation and accumulation of transferrin receptor at the plasma membrane. N-myristoyltransferase inhibition activates the DNA damage response and potentiates cell death induced by platinum doublet chemotherapy in (KL / K)MUTlung carcinoma cells. Parthanatos is characterized by extensive oxidative stress and DNA damage (43). To investigate if NMTi caused DNA damage in (KL / K)MUTlung cancer cells, we stained cells with the DNA damage response marker phospho-H2A.X, which localizes at DNA repair foci. Notably, NMTi increased phospho-H2A.X positive foci in (KL / K)MUTH1792 lung carcinoma (FIG.6A), and xenografted H460 tumors from mice treated with PCLX-001 (FIG.6B). The induction of DNA damage by NMTi suggests that it could sensitize cancer cells to DNA damaging chemotherapeutics. To test this hypothesis, we selected Cisplatin and Pemetrexed, chemotherapeutics to which (KL / K)MUTHCC44 and H1792 are resistant (Genomics of Sensitivity in Cancer). Treatment with PCLX-001 (50 nM) decreased the viability in response to 1.25 μM Cisplatin by ~ 25% in HCC44 and by ~ 20% in H1792 (FIG.6C). Treatment with PCLX-001 (50 nM) decreased the viability of in response to 5 μM Pemetrexed by ~ 35% in HCC44 and ~ 25% in H1792 (FIG.6C). When PCLX-001 (125 nM) was combined with 5 μM Pemetrexed, the viability of cells treated with 0.6 μM Cisplatin decreased by ~ 40% in HCC44 cells and ~ 30% in H1792 cells (FIG.6C). Taken together, our data indicates that NMTi causes DNA damage in (KL / K)MUTlung carcinoma cells and sensitizes them to platinum doublet chemotherapy. Our findings warrant further investigation of the efficacy of combining platinum-based chemotherapy and NMTi in preclinical models of cancer. Atty. Docket No.: LABIO-006WO Mitochondria are a key target of N-myristoyltransferase inhibitors. To investigate how NMTi causes parthanatos in (KL / K)MUTlung carcinoma cells, we wondered which biological processes were altered by NMTi treatment in H1792 cells. Analysis of our global proteomics data in H1792 cells revealed that “NADH dehydrogenase assembly” and “mitochondria respiratory chain complex assembly” were among the top three biological process overrepresented in control vs. NMTi-treated cells (FIG.19A), indicating that mitochondria are a key target of NMTi. In agreement with previous reports (7,62,63), the abundance of NDUFAF4, a myristoylated protein that participates in the assembly of the mitochondrial respiratory complex I, decreased after NMT inhibition in (KL / K)MUTcells (FIG. 19B). siRNA-mediated silencing of NDUFAF4 in NMTi-sensitive lung carcinoma cells caused mitochondrial fragmentation but did not alter cell viability as demonstrated by lack of morphological features of cell death, including DNA fragmentation (FIG.19C). We concluded that loss of NDUFAF4 is unlikely to be a major contributor to NMTi-induced cell death in (KL / K)MUTlung carcinoma cells. Next, we compared the ultrastructure of mitochondria in control and NMTi-treated H1792 cells. After 24 hours of NMTi treatment, mitochondrial transitioned from an orthodox ultrastructure with elongated cristae to a condensed-like ultrastructure in which matrix volume decreases and cristae volume expands (FIG.7A and FIG.19D), a state associated with transition to increased ATP production (64,65). Notably, at 72 hours of treatment, mitochondria appear highly electron-dense with the vast majority lacking distinguishable internal membranes, an indication of extensive widespread mitochondrial damage (Fig.6A and FIG.19D). Our differential proteomic data identified 539 proteins from a total of 1,119 mitochondria- related proteins in the Human Protein Atlas. From these, the abundance of 179 (33.2%) was significantly altered by NMTi treatment after adjusting for false discovery: 79 increased and 100 decreased. Gene Ontology analysis showed enrichment in mitochondrial matrix proteins and decrease in mitochondrial membrane proteins in drug-treated cells (FIG.19E). We reasoned that imbalance in matrix vs. membrane mitochondrial protein content might reflect defective import of proteins into the matrix. The outer mitochondrial membrane proteins TOM40 (Translocase of the Outer Mitochondrial Membrane 40) and SAM50 (Sorting and Assembly Machinery Component 50) participate in mitochondrial protein import and are NMT targets (66). SAM50 binds to Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 3 (CHCHD3), a component of the mitochondrial contact site and cristae organizing system (MICOS) complex, which is also an NMT target (66). Surprisingly, at 72 hours of NMTi treatment we found only a Atty. Docket No.: LABIO-006WO modest decrease of around 30% in the abundance of TOM40 and no changes in SAM50 or CHCHD3 in lysates from H1792 cells (FIG.19F). Immunofluorescence revealed that TOM40, SAM50 and CHCHD3 remained largely localized at mitochondria in NMTi-treated cells, also arguing against mis-localization. Next, we search our proteomics data for other candidates whose loss-of-function could impact mitochondrial protein import. We focused on mitochondrial membrane associated proteins and identified 119 mitochondrial membrane proteins from a total of 294 found in the Human Protein Atlas. From these, the abundance of 12 (10%) was significantly altered by NMTi treatment after adjusting for false discovery (FIG.7B). Of particular interest was the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A), whose abundance was reduced 2.5-fold by NMTi treatment. TIM17 subunits A and B are essential components of the TIM23 inner mitochondrial membrane translocase, one of the two complexes that import nuclear-encoded proteins to the mitochondria (FIG.7C). Dependency on TIM17A is a key determinant of sensitivity to N- myristoyltransferase inhibitors in lung carcinoma. We explored the TCGA LUAD dataset and found a significant association between elevated TIM17A transcript levels and decreased survival probability (FIG.7D), indicating that TIM17A function may be relevant to lung carcinoma progression. Next, we analyzed TIM17A protein abundance in (KL / K)MUTlung cancer cells treated with NMTi and confirmed that TIM17A levels decreased 24 hours after NMTi treatment in H460 (FIG.7E) and H1792 (Fig. S11A), and 48 hours after treatment in HCC44 cells (Fig. S11B). The expression of TIM17B subunit was only minimally altered by NMTi (FIG.7E and Fig. S11A) even at 72 hours. The mitochondrial matrix protein HSP60 and the transmembrane protein TOM20, which are commonly used mitochondrial markers, remained unchanged or slightly decreased at 72 hours of treatment in H460 (FIG.7F) or H1792 cells (Fig. S11A). Likewise, the mitochondrial membrane protein SAM50 was not altered by NMTi treatment in HCC44 cells (Fig. S11B). Resistant (KL / K)WTlung carcinoma cells also showed decreased TIM17A at 72 hours of treatment with NMTi (FIG.8A), but not at earlier time points (Fig. S11C, D). Because NMTi caused loss of TIM17A in sensitive and resistant cells, but only the former die, we reasoned that NMTi sensitive lung carcinoma cells might have a higher reliance on TIM17A. To explore this possibility, we used the Cancer Dependency Map portal (CRISPR Chronos algorithm), which assigns an estimated CRISPR DepMap Score for each gene in a way that negative values suggest decreased cell viability. Notably, TIM17A dependency scores Atty. Docket No.: LABIO-006WO for NMTi sensitive cells HCC44, H460 and H1792 were lower when compared with the dependency scores of resistant H522, H1650 and H1437 (FIG.8B). This suggests that (KL / K)MUTlung cancer cells not only are more sensitive to NMTi but also more dependent on TIM17A for survival. Next, we compared NMTi EC50data deposited in the Genomics of Drug Sensitivity in Cancer portal with TIM17A dependency data (CRISPR Chronos) deposited in the Cancer Dependency Map and found an unexpected significant correlation (⍴ = -0.43, P=0.006) between NMTi sensitivity and TIM17A dependency in lung carcinoma cells (FIG.8C). To demonstrate experimentally that (KL / K)MUTare more dependent on TIM17A than (KL / K)WTcells, we used two complementary genetic strategies. We knocked-down TIM17A by transfection of an siRNA pool into H1792 (KL / K)MUTand H522 (KL / KWT) cells and analyzed cell viability. In agreement with the CRISPR score data, loss of TIM17A induced cell death in H1792 cells but did not affect the viability of H522 (FIG.8D). Next, we generated H460 and H522 cells expressing Tet-inducible TIM17A shRNA and used them to evaluate colony formation ability. In agreement with the first approach, colony forming ability was strongly decreased by TIM17A loss in H460 cells, but only modestly decreased in H522 cells (FIG.8E). Taken together, our data reveals an unexpected correlation between sensitivity to NMT inhibition and dependency on TIM17A in lung carcinoma cells. Genetic targeting of TIM17A induces mitochondrial ferrous iron accumulation and markers of parthanatos in (KL / K)MUTlung carcinoma cells. TIM17A is not myristoylated, thus, it is unclear how NMTi decreases TIM17A levels. We mimicked oxidative stress by treating cells with 4-hydroxynonenal (4HNE), a byproduct of lipid peroxidation. Notably, a short pulse of 4-HNE caused a modest decrease of TIM17A, accompanied by a compensatory increase in TIM17B abundance in H1792 cells (FIG.21A). Furthermore, a short pulse of 4-HNE caused extensive protein PARylation (Fig.21B), indicating that lipid peroxidation contributes to TIM17A loss and PARP activation in (KL / K)MUTlung carcinoma cells. Next, we wondered whether loss of TIM17A in NMTi sensitive, TIM17A-dependent (KL / K)MUTlung cancer cells could cause mitochondrial ferrous iron overload. We transfected non-targeting control and two different TIM17A-specific siRNA oligos in H1792 (sensitive) and H522 (resistant) cells and analyzed the accumulation of ferrous iron in mitochondria. Notably, sensitive but not resistant cells showed increased mitochondrial ferrous iron when TIM17A was silenced (FIG.9A). These data suggests that the susceptibility of (KL / K)MUTcells to mitochondrial ferrous iron overload could be a determinant of TIM17A dependency. Accordingly, Atty. Docket No.: LABIO-006WO TIM17A silencing in (KL / K)MUTcells (which induced cell death, FIG.8D, E) also increased protein PARylation (FIG.9B), activated the DNA damage response (FIG.9C) and caused AIF nuclear accumulation (FIG.9D). Taken together, our data indicate that loss of TIM17A in TIM17A-dependent lung cancer cells causes oxidative stress and contributes to the induction of parthanatos. We propose a model in which (KL / K)MUTbut not (KL / K)WTlung carcinoma cells depend on NMT activity to maintain cellular iron homeostasis. Inhibition of NMT caused mitochondrial iron overload, increased ROS generation and led to widespread lipid peroxidation and DNA damage by a mechanism at least in part mediated by loss of the mitochondrial transporter subunit TIM17A. Excessive lipid peroxidation, which in turn led to further TIM17A loss in a vicious cycle, sustained oxidative stress, activated PARP and caused parthanatos in (KL / K)MUTlung carcinoma cells (FIG.9E). Discussion We report here that NMT inhibition causes death by parthanatos in a subset of lung carcinoma cells through TIM17A loss, mitochondrial ferrous iron overload and oxidative stress- induced DNA damage and PARP activation. We show that NMT inhibitors are effective as single agents against lung carcinomas with concurrent LKB1 and / or KEAP1 mutations in a KRAS mutant background (KL / K)MUTand sensitize cells with these mutations to platinum-based chemotherapy. NMT1 was previously associated with lower survival in lung adenocarcinoma (67) and our updated TCGA data analysis is consistent with that study. Some lung carcinoma cells included in this study were previously found to be sensitive to PCLX-001 (18). The reason for the sensitivity of (KL / K)MUTlung carcinoma cells to NMT inhibition is unknown, as none of these tumor drivers are myristoylated. Additional research is necessary to dissect the specific molecular mechanisms by which this mutational signature confers sensitivity to NMTi. Nevertheless, our data indicates that a subset of highly aggressive and difficult-to-treat lung carcinomas rely on NMT activity for survival, uncovering a novel potential therapeutic approach for these aggressive tumors. It is unclear how NMTi alters the distribution of TfR1, but a similar enrichment in membrane localization of TfR1 occurs in cells undergoing ferroptosis (56), suggesting a role for oxidative stress and lipid peroxidation in the disruption of TfR1 trafficking downstream NMTi treatment. Atty. Docket No.: LABIO-006WO Mitochondrial ferrous iron overload induced by NMTi appeared linked to TIM17A loss. Understanding the exact mechanism by which TIM17A loss induces ferrous iron accumulation in mitochondria requires further investigation, but we could speculate that decreased mitochondrial protein import caused by loss of TIM17A alters the synthesis of iron-sulfur clusters or heme- containing proteins. Indeed, most genetic diseases causing mitochondrial iron accumulation are linked to defective synthesis of iron sulfur clusters or heme (68). Likewise, it will be relevant to investigate why the accumulation of ferrous iron in mitochondria in response to NMTi happens in (KL / K)MUTbut not (KL / K)WTlung carcinoma cells. One possibility is that (KL / K)MUTcells are more reliant on iron sulfur clusters and / or heme-containing proteins to sustain their high proliferative rates, and thus, a larger amount of ferrous iron is accumulated in their mitochondria if the assembly of these prosthetic groups into proteins fails. In agreement, heme has been shown to sustain oxidative phosphorylation and tumor progression in lung carcinoma (69,70). Our proteomic data indicating decreased expression of various electron transport chain components after NMTi treatment has been noted before (17,63). This could be a consequence of defective mitochondrial protein import and cause decreased ATP generation. Our observation that NMTi causes a switch in mitochondria from orthodox to compact state (which has been linked to increased ATP production (64)) suggests a compensatory effect. In agreement, we previously showed that autophagy and lysosomal-associated degradation are defective in lung carcinoma cells treated with NMTi (16), which could contribute to metabolic stress. In addition, NMTi has been shown to decrease oxygen consumption (62), suggesting defective oxidative phosphorylation. Although loss of TIM17A represents a pro-survival mechanism that promotes stress resistance by maintaining mitochondrial proteostasis (35), we show here that some cancer cells are dependent on TIM17A expression for survival, likely because loss of TIM17A in these cells, but not others, causes mitochondrial ferrous iron accumulation and oxidative stress. Thus, TIM17A appears to be a potential therapeutic target in a subset of lung carcinomas and possibility other cancers. It will be important to dissect the mechanism by which NMTi causes TIM17A loss. One possibility is that TIM17A decreases in response to stress caused by general lack of myristoylation of newly synthesized proteins. In agreement with this hypothesis, NMTi has been shown to induce endoplasmic reticulum stress in cancer cells (17). We discovered that NMTi causes parthanatos. NMTi lead to PARP1 activation, increased protein PARylation, and translocation of AIF and MIF to the nucleus. The parthanatos inhibitor Olaparib, but not inhibitors of apoptosis, ferroptosis, necroptosis or pyroptosis, partially rescued cell death induced by NMTi. We and others have shown features of apoptosis in cells Atty. Docket No.: LABIO-006WO treated with NMTi (16-18). Although we cannot completely rule out that NMT inhibition causes some apoptosis, the lack of rescue with caspase inhibitors suggests that parthanatos is the main death mechanism downstream of NMTi treatment in (KL / K)MUTlung carcinoma cells. Notably, cells dying by parthanatos have been shown to be Annexin V-positive, and experience caspase activation, although it is dispensable for death (43,44). Excessive ROS and DNA damage are known activators of PARP in parthanatos. Thus, mitochondrial ferrous iron accumulation and the consequent increase in ROS generation and lipid peroxidation are likely the cause of DNA damage and PARP activation. Notably, we observed that 4-HNE increased PARylation in lung carcinoma cells, suggesting that lipid peroxidation can also activate PARP. Parthanatos is better characterized in neurodegenerative diseases, but it can also occur in cancer cells. As such, the induction of parthanatos could kill apoptosis and ferroptosis resistant cancer cells, offering obvious therapeutic advantages. However, to date, only a few compounds have been shown to induce parthanatos in cancer (71- 73). Our finding that NMT inhibitors selectively induce parthanatos in a subset of lung carcinoma cells and possibly other cancer types, offers an opportunity to better understand the significance of parthanatos in cancer and how to induce it for therapy. Acknowledgments: We thank Lucy Weaver, Aakash Kondaka and Lia Osipyan for help with image acquisition and / or quantification. We are grateful to Dr. Steven Dubinett (UCLA) and Dr. Carla Koehler (UCLA) for scientific advice on this project. We thank Dr. Chong Hyun Chang and acknowledge the use of the ICP-MS facility within the NPCL in CNSI at UCLA; Dr. Guillaume Castillon and the UC San Diego, Cellular and Molecular Medicine Electron Microscopy Core (UCSD-CMM-EM Core, RRID:SCR022039) for equipment access and technical assistance. The Core is supported in part by the NIH Award number S10OD023527. We thank Chun-Teng Huang and acknowledge the use of the Viral Core Facility at the SBP Medical Research Institute with support from the NIH NCI P30CA030199. This work has been supported by NIH GM089778 award to J.W., NIH CA208642-06 award to D.B.S., UCLA JCCC Seed Grant Award, UCLA CTSI UL1TR001881 Voucher Award, Kenneth T. & Eileen L. Norris Foundation Award, and The University of California Regents TRDRP Award T32IP5106 to B.D. References 1. Wright MH, Heal WP, Mann DJ, Tate EW. Protein myristoylation in health and disease. J Chem Biol 2010;3:19-35 Atty. Docket No.: LABIO-006WO 2. Duronio RJ, Reed SI, Gordon JI. 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Journal of Internal Medicine 2020;287:645-64 Atty. Docket No.: LABIO-006WO 66. Utsumi T, Matsuzaki K, Kiwado A, Tanikawa A, Kikkawa Y, Hosokawa T, et al. Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PLoS One 2018;13:e0206355 67. Liang J, Xu ZX, Ding Z, Lu Y, Yu Q, Werle KD, et al. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat Commun 2015;6:7926 68. Rouault TA. Mitochondrial iron overload: causes and consequences. Curr Opin Genet Dev 2016;38:31-7 69. Hooda J, Cadinu D, Alam MM, Shah A, Cao TM, Sullivan LA, et al. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells. PLoS One 2013;8:e63402 70. Sohoni S, Ghosh P, Wang T, Kalainayakan SP, Vidal C, Dey S, et al. Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells. Cancer Research 2019;79:2511-25 71. Zhang Y, Zhang C, Li J, Jiang M, Guo S, Yang G, et al. Inhibition of AKT induces p53 / SIRT6 / PARP1-dependent parthanatos to suppress tumor growth. Cell Commun Signal 2022;20:93 72. Li C, Zhang J, Wu Q, Kumar A, Pan G, Kelvin DJ. Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer. Mol Cancer Ther 2023;22:306-16 73. Liu L, Liu B, Guan G, Kang R, Dai Y, Tang D. Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1. Biochem Biophys Res Commun 2022;606:68-74 In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as Atty. Docket No.: LABIO-006WO “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. As will be understood by one skilled in the art, for any and all purposes, such as in terms Atty. Docket No.: LABIO-006WO of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in Atty. Docket No.: LABIO-006WO the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked.

Claims

Atty. Docket No.: LABIO-006WO WHAT IS CLAIMED IS:

1. A method of treating a subject for cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor and a proteasome inhibitor to treat the subject for cancer.

2. The method according to Claim 1, wherein the N- myristoyltransferase inhibitor is DDD86481.

3. The method according to Claims 1 or 2, wherein the proteasome inhibitor is bortezomib.

4. The method according to any of the preceding claims, wherein the N- myristoyltransferase inhibitor and proteasome inhibitor are administered to the subject simultaneously.

5. The method according to Claim 4, wherein the N-myristoyltransferase inhibitor and a proteasome inhibitor are administered to the subject in a single pharmaceutical composition.

6. The method according to any of Claims 1 to 3, wherein the N-myristoyltransferase inhibitor and proteasome inhibitor are administered to the subject sequentially.

7. The method according to any of the preceding claims, wherein the subject is a mammal.

8. The method according to Claim 7, wherein the mammal is a human.

9. The method according to any of the preceding claims, wherein the cancer is lung cancer.

10. A pharmaceutical composition comprising a synergistically effective amount of a N- myristoyltransferase inhibitor and a proteasome inhibitor.Atty. Docket No.: LABIO-006WO 11. The pharmaceutical composition according to Claim 10, wherein the N- myristoyltransferase inhibitor is selected from DDD85646, DDD86481 and IMP-1088.

12. The pharmaceutical composition according to Claim 10, wherein the N- myristoyltransferase inhibitor is DDD86481.

13. The pharmaceutical composition according to any one of Claims 10-12, wherein the proteasome inhibitor is bortezomib.

14. A method of killing an apoptosis-resistant lung carcinoma cell, the method comprising: contacting the cell with a N-myristoyltransferase inhibitor to kill the apoptosis- resistant lung carcinoma cell.

15. The method according to Claim 14, wherein the method results in one or more of mitochondrial ferrous iron overload, increased ROS generation, excessive lipid peroxidation and PARP activation in the apoptosis-resistant lung carcinoma cell.

16. The method according to any of Claims 14 to 15, wherein the killing comprises parthanatos.

17. The method according to any of Claims 14-16, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481 and IMP-1088.

18. The method according to any of Claims 14-17, wherein the apoptosis-resistant lung carcinoma cell comprises a KRAS / LKB / KEAP1 mutational signature.

19. The method according to any of Claims 14-18, wherein the apoptosis resistant lung carcinoma cell exhibits increased dependency on TIM17A relative to a control.

20. The method according to any of Claims 14-18, wherein the method comprises, prior to said contacting, determining that the lung carcinoma cell exhibits increased TIM17A dependence relative to a control.Atty. Docket No.: LABIO-006WO 21. The method according to any of Claims 14-20, wherein the method further comprises contacting the cell with a chemotherapeutic agent.

22. The method according to Claim 21, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent.

23. The method according to Claim 22, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof.

24. The method according to Claim 21, wherein the chemotherapeutic agent comprises one or more platinum-based compounds.

25. The method according to Claim 21, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound.

26. The method according to any of Claims 14-25, wherein the cell is in vivo and the method comprises administering the N-myristoyltransferase inhibitor to a subject comprising the cell.

27. The method according to Claim 26, wherein the subject is a mammal.

28. The method according to Claim 27, wherein the mammal is a human.

29. The method according to any of Claims 14-25, wherein the cell is in vitro.

30. The method according to any of Claims 14-29, wherein the apoptosis-resistant lung carcinoma cell is non-small cell lung carcinoma (NSCLC) cell.

31. A method of treating a subject for therapy resistant lung cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor to treat the subject for therapy-resistant lung cancer.Atty. Docket No.: LABIO-006WO 32. The method according to Claim 31, wherein the therapy-resistant lung cancer is characterized by the presence of apoptosis-resistant lung cancer cells.

33. The method according to Claim 32, wherein the method results in one or more of mitochondrial ferrous iron overload, increased ROS generation, excessive lipid peroxidation and PARP activation in the apoptosis-resistant lung carcinoma cells.

34. The method according to any of Claims 31-33, wherein the method comprises inducing parthanatos in lung cancer cells.

35. The method according to any of Claims 31-34, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088.

36. The method according to any of Claims 31-35, wherein the method further comprises administering to the subject a chemotherapeutic agent.

37. The method according to Claim 36, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent.

38. The method according to Claim 37, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof.

39. The method according to any of Claims 31-38, wherein the subject comprises a KRAS / LKB / KEAP1 mutational signature.

40. The method according to Claim 39, wherein the method comprises assaying the subject for the KRAS / LKB / KEAP1 mutational signature.

41. The method according to any of Claims 31-40, wherein the subject is a mammal.

42. The method according to Claim 41, wherein the mammal is a human.

43. The method according to any of Claims 31-42, wherein the lung cancer is non-small cell lung carcinoma (NSCLC).Atty. Docket No.: LABIO-006WO 44. A method of treating a subject for cancer, the method comprising: administering to the subject a N-myristoyltransferase inhibitor and a chemotherapeutic agent to treat the subject for cancer.

45. The method according to Claim 44, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088.

46. The method according to Claim 44, wherein the N- myristoyltransferase inhibitor is DDD86481.

47. The method according to any of Claims 44-46, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent.

48. The method according to Claim 47, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof.

49. The method according any of Claims 44-46, wherein the chemotherapeutic agent comprises one or more platinum-based compounds.

50. The method according any of Claims 44-46, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound.

51. The method according to any of Claims 44-50, wherein the N-myristoyltransferase inhibitor and a chemotherapeutic agent are administered to the subject simultaneously.

52. The method according to Claim 51, wherein the N-myristoyltransferase inhibitor and chemotherapeutic agent are administered to the subject in a single pharmaceutical composition.

53. The method according to any of Claims 44-50, wherein the N-myristoyltransferase inhibitor and chemotherapeutic agent are administered to the subject sequentially.

54. The method according to any of Claims 44-53, wherein the subject is a mammal.Atty. Docket No.: LABIO-006WO 55. The method according to Claim 54, wherein the mammal is a human.

56. The method according to any of Claims 44-55, wherein the cancer is lung cancer.

57. The method according to Claim 56, wherein the lung cancer is non-small cell lung carcinoma (NSCLC).

58. The method according to any of Claims 44-57, wherein the subject comprises a KRAS / LKB / KEAP1 mutational signature.

59. The method according to Claim 58, wherein the method comprises assaying the subject for the KRAS / LKB / KEAP1 mutational signature.

60. A pharmaceutical composition comprising a synergistically effective amount of a N- myristoyltransferase inhibitor and a chemotherapeutic agent.

61. The pharmaceutical composition according to Claim 60, wherein the N- myristoyltransferase inhibitor is DDD86481.

62. The pharmaceutical composition according to Claim 60 or Claim 61, wherein the chemotherapeutic agent is a DNA damaging chemotherapeutic agent.

63. The pharmaceutical composition according to Claim 62, wherein the DNA damaging chemotherapeutic agent is selected from Pemetrexed, cisplatin and combinations thereof.

64. The pharmaceutical composition according to Claim 60 or Claim 61, wherein the chemotherapeutic agent comprises one or more platinum-based compounds.

65. The pharmaceutical composition according to Claim 60 or Claim 61, wherein the chemotherapeutic agent comprises pemetrexed and a platinum-based compound.

66. A method of treating a subject for lung cancer, the method comprising:Atty. Docket No.: LABIO-006WO administering to the subject a N-myristoyltransferase inhibitor to treat the subject for lung cancer, wherein the lung cancer is TIM17A dependent.

67. The method of Claim 66, wherein the method comprises, prior to said administering, determining that the lung cancer exhibits TIM17A dependence.

68. The method according to Claim 66 or Claim 67, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088.

69. The method according to Claim 66 or Claim 67, wherein the N- myristoyltransferase inhibitor is DDD86481.

70. The method according to any of Claims 66-69, wherein the subject is a mammal.

71. The method according to Claim 70, wherein the mammal is a human.

72. The method according to any of Claims 66-71, wherein the lung cancer is non-small cell lung carcinoma (NSCLC).

73. A method of killing lung cancer cell, the method comprising: contacting the lunger cancer cell with a N-myristoyltransferase inhibitor to kill the cell, wherein the cell is TIM17A dependent.

74. The method of Claim 73, wherein the method comprises, prior to said contacting, determining that the lung cancer cell exhibits increased TIM17A dependence relative to a control.

75. The method according to Claim 73 or Claim 74, wherein the N-myristoyltransferase inhibitor is selected from DDD85646, DDD86481, and IMP-1088.

76. The method according to Claim 73 or Claim 74, wherein the N- myristoyltransferase inhibitor is DDD86481.Atty. Docket No.: LABIO-006WO 77. The method according to any of Claims 73-76, wherein the cell is in vivo and the method comprises administering the N-myristoyltransferase inhibitor to a subject comprising the cell.

78. The method according to any of Claims 73-76, wherein the cell is in vitro.

79. The method according to any of Claims 73-78, wherein the cell is a mammalian cell.

80. The method according to any of Claims 73-78, wherein the cell is a human cell.

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