Application of copper death inducer in preparation of medicine for treating osimertinib-resistant non-small cell lung cancer

Abstract

The invention provides application of a copper death inducer in preparation of a medicine for treating osimertinib-resistant non-small cell lung cancer, and belongs to the technical field of treatment of non-small cell lung cancer. According to the invention, through high-throughput drug screening, the copper death inducer copper diethyl dithiocarbamate (CuET) and osimertinib are combined for use, so that a remarkable synergistic anti-cancer effect is achieved; furthermore, through detection of a wild type and osimertinib drug-resistant cell line model, an osimertinib sensitive and drug-resistant patient-derived organoid and a mouse xenotransplantation model, it is found that the anti-tumor effect of osimertinib can be remarkably enhanced through copper death induction, and osimertinib drug resistance is overcome. According to the technical scheme provided by the invention, osimertinib drug-resistant non-small cell lung cancer cells can be effectively killed, the curative effect of osimertinib in sensitive and drug-resistant models is remarkably enhanced, and an application scene is provided for copper death in tumor treatment.

Description

Technical Field

[0001] This invention belongs to the field of non-small cell lung cancer treatment technology, and particularly relates to the application of copper death inducers in the preparation of drugs for treating osimertinib-resistant non-small cell lung cancer. Background Technology

[0002] Lung cancer, the leading cause of both morbidity and mortality worldwide, poses a serious threat to human health, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. In NSCLC, mutations in the human epidermal growth factor receptor (EGFR) gene are one of the most prevalent driver mutations, particularly prevalent in the Chinese population, where the incidence rate is as high as approximately 50%.

[0003] The advent of osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has brought significant benefits to patients with EGFR-mutant NSCLC, effectively prolonging progression-free survival and becoming a first-line standard treatment for this group. However, almost all patients treated with osimertinib eventually develop acquired resistance, severely limiting the long-term efficacy of the drug and overall patient survival. Among the many factors leading to resistance, bypass activation pathway-mediated resistance affects 46% of patients, but currently there are no specific interventions for this resistance mechanism, resulting in extremely limited clinical treatment options. Therefore, there is an urgent need to develop novel treatment strategies that can bypass the EGFR pathway and reverse or overcome resistance. Currently, the main technical solutions for overcoming EGFR-TKI osimertinib resistance fall into the following categories: Targeted drug replacement: This involves using next-generation TKIs for treatment, but this method mostly still relies on EGFR or its upstream and downstream pathways, making it difficult to overcome bypass activation resistance mechanisms and carrying the risk of cumulative toxicity. Combination chemotherapy or immunotherapy: such as combining platinum-based chemotherapy or PD-1 inhibitors to delay progression, however, this regimen has severe side effects, low selectivity, and limited long-term efficacy.

[0004] Copper death, a regulatory cell death mechanism first proposed by Tsvetkov et al. in *Science* in 2022, relies on key factors in the mitochondrial lipid acylation pathway, such as FDX1 and DLAT. Currently, international research on copper death is still in its early stages, with subsequent studies gradually expanding its applications in areas such as radiotherapy enhancement, bacterial eradication, and nanomedicine. In China, research on copper death has also gradually developed in recent years, mainly focusing on molecular mechanisms and basic research, lacking systematic exploration of therapeutic applications. Notably, in 2023, the applicant was the first to systematically summarize the role of copper death in cancer-related pathways and its clinical translational potential. This review was published in *Molecular Cancer* and has been cited 503 times, ranking as a JCR highly cited paper (1%) and a hot paper (0.1%). A 2025 study in *Cancer Cell* reported that inducing copper death in tumor cells can enhance the effect of radiotherapy, but the role of copper death in osimertinib resistance has not yet been reported. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a synergistic treatment strategy based on the copper death induction mechanism, which utilizes copper death inducers such as CuET to enhance the anti-tumor effect of osimertinib in EGFR-mutant non-small cell lung cancer, thereby overcoming the drug resistance problem existing in current treatments.

[0006] This invention aims to solve the following technical challenges encountered in the existing osimertinib treatment: 1) overcoming acquired resistance to osimertinib; 2) achieving synergistic anticancer effects of CuET and osimertinib, improving efficacy and delaying the onset of resistance; 3) laying the theoretical and technical foundation for the subsequent development of copper death-targeted drug delivery systems.

[0007] This invention, through high-throughput drug screening, discovered that the combination of copper death inducer copper and osimertinib has a significant synergistic anticancer effect. This discovery provides an effective new strategy for overcoming osimertinib resistance and has important scientific significance and clinical translation prospects.

[0008] This invention provides the application of copper death inducers in the preparation of drugs for treating osimertinib-resistant non-small cell lung cancer.

[0009] Preferably, the copper death inducer is used in combination with osimertinib.

[0010] Preferably, the copper death inducer comprises copper diethyl dithiocarbamate (CuET).

[0011] Preferably, the dosage of copper diethyl dithiocarbamate (CuET) is 1–2 mg / kg / 2 days.

[0012] Preferably, the dosage of osimertinib is 4–6 mg / kg / day.

[0013] This invention provides a combination drug for treating non-small cell lung cancer or osimertinib-resistant non-small cell lung cancer, comprising the copper death inducer copper diethyl dithiocarbamate (CuET) and osimertinib.

[0014] This invention provides the application of copper death inducers in the preparation of reagents for inhibiting the proliferation of non-small cell lung cancer cell lines, wherein the copper death inducers include copper diethyl dithiocarbamate (CuET).

[0015] Preferably, the non-small cell lung cancer cell lines include one or more of HCC827, H1975, HCC827 OR, and H1975 OR cells.

[0016] Preferably, the concentration of copper diethyl dithiocarbamate (CuET) is 0.1–1 μM.

[0017] Compared with existing technologies, this invention has the following beneficial effects: This invention provides the application of a copper death inducer in the preparation of a drug for treating osimertinib-resistant non-small cell lung cancer. Through testing on cell lines, osimertinib-resistant models, patient-derived organoids, and mouse xenograft models, this invention found that copper death induction can significantly enhance the anti-tumor effect of osimertinib, especially showing a significant synergistic effect in resistant models. Its mechanism involves inhibiting AKT phosphorylation levels, upregulating the copper death marker oligomerization DLAT, and inducing programmed cell death. This invention has the following technical effects: 1) achieving effective killing of osimertinib-resistant non-small cell lung cancer cells; 2) significantly enhancing the efficacy of osimertinib in both sensitive and resistant models; 3) expanding the application scenarios of copper death in tumor treatment.

[0018] Specifically, in drug-resistant cell lines (HCC827OR, H1975OR), the combined treatment of CuET and osimertinib showed a significant synergistic killing effect. Synergistic score analysis showed that the two had a high synergistic effect (synergistic score >15, p<0.001). The combined treatment of the two drugs could significantly inhibit cell proliferation and induce cell death. The combined treatment of the two drugs induced the activation of the copper death and apoptosis pathways in cells, and the effect was much higher than that of either drug alone.

[0019] In osimertinib-resistant organoids, the CuET-osimertinib combination therapy group showed significant antitumor effects, with significantly smaller organoid volume and decreased survival compared to the monotherapy group. This combination also further enhanced the efficacy of osimertinib in sensitive organoids, suggesting that CuET has a broad-spectrum sensitizing effect. The experimental results indicate that copper death inducers can enhance osimertinib sensitivity at the organoid level, supporting its preclinical application value.

[0020] Animal experiments showed that, compared with the monotherapy group, CuET combined with osimertinib significantly inhibited tumor growth, with a significant decrease in tumor volume and terminal tumor weight (p<0.001). The animals treated with CuET combined with osimertinib were in good condition, with no obvious toxicity or weight loss, indicating that the combination therapy has good safety. The animal experiment results further confirmed the application potential of copper death inducers in overcoming osimertinib resistance at the in vivo level, which has important translational medicine value. Attached Figure Description

[0021] Figure 1 To validate the effect of CuET on osimertinib in high-throughput drug screening experiments;

[0022] Figure 2 To screen for sensitivity of programmed cell death pathways and clarify that osimertinib resistance is susceptible to copper death, the left figure is a heatmap of cell viability response after 72 hours of treatment with various cell death inducers, and the right figure is a biomarker of different programmed cell death in cells.

[0023] Figure 3 To clarify the synergistic effect of copper death in inducing osimertinib to overcome osimertinib resistance in cell experiments, from left to right: CuET and osimertinib combined effect index experiment, drug sensitivity test, Incucyte real-time cell proliferation assay and colony formation assay;

[0024] Figure 4 To clarify in organoid experiments that copper death induces synergistic effects with osimertinib to overcome osimertinib resistance;

[0025] Figure 5 To clarify in animal experiments that copper-induced death synergistically overcomes osimertinib resistance. Detailed Implementation

[0026] This invention provides the application of copper death inducers in the preparation of drugs for treating osimertinib-resistant non-small cell lung cancer.

[0027] In this invention, the copper death inducer is preferably used in combination with osimertinib; the copper death inducer preferably includes copper diethyl dithiocarbamate (CuET).

[0028] In this invention, taking nude mouse experiments as an example, the preferred dosage of copper diethyl dithiocarbamate (CuET) is 1-2 mg / kg / 2 days, more preferably 1.2-1.8 mg / kg / 2 days, and even more preferably 1.5 mg / kg / 2 days; the preferred treatment method for copper diethyl dithiocarbamate (CuET) is intraperitoneal injection.

[0029] In this invention, taking nude mouse experiments as an example, the dosage of osimertinib is 4-6 mg / kg / day, preferably 4.5-5.5 mg / kg / day, and more preferably 5 mg / kg / day.

[0030] This invention provides a combination drug for treating non-small cell lung cancer or osimertinib-resistant non-small cell lung cancer, comprising the copper death inducer copper diethyl dithiocarbamate (CuET) and osimertinib.

[0031] This invention utilizes CuET to induce copper death in cells, which works synergistically with osimertinib to jointly intervene in drug-resistant tumor cells from multiple targets, thereby improving the efficacy of osimertinib and reversing the drug-resistant phenotype.

[0032] The combination drugs involved in this invention include:

[0033] Copper death inducer CuET (Copper diethyldithiocarbamate): induces FDX1 / DLAT-dependent copper death in cells.

[0034] Osimertinib (EGFR-TKI): Used to inhibit EGFR mutation-driven signaling pathways.

[0035] This combination drug can be validated in various systems, including in vitro (cell lines), organoid models, and in vivo (mouse xenograft tumors), and can be further developed into a combination therapy strategy or a targeted delivery formulation.

[0036] In this invention, the combination drugs are implemented in the form of physical mixing or sequential administration.

[0037] This invention provides the application of copper death inducers in the preparation of reagents for inhibiting the proliferation of non-small cell lung cancer cell lines, wherein the copper death inducers include copper diethyl dithiocarbamate (CuET).

[0038] In this invention, the preferred non-small cell lung cancer cell lines include one or more of HCC827, H1975, HCC827 OR, and H1975 OR cells. In this invention, the final concentration of copper diethyldithiocarbamate (CuET) is preferably 0.1–1 μM, the initial concentration is preferably 0.3–0.7 μM, more preferably 0.4–0.6 μM, and even more preferably 0.5 μM; in this invention, the final concentration of osimertinib is preferably 0.5–10 μM, preferably set according to the specific cell IC50.

[0039] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0040] Example 1

[0041] Screening has shown that copper death induction can overcome osimertinib resistance in non-small cell lung cancer.

[0042] 1. High-throughput drug screening experiments validated that CuET enhances the efficacy of osimertinib.

[0043] (1) Combination screening design

[0044] 1) Lung adenocarcinoma cell lines were seeded at 3000 cells per well in 96-well plates, and two groups of conditions were set up: CuET pretreatment group (final concentration 0.5 μM) and blank control group;

[0045] 2) Add 5 μM of 3113 FDA-approved drugs (selleck L2000 FDA-Approved Drug Library-II) to both groups and incubate for 72 hours;

[0046] 3) The synergistic effect of each drug on the CuET background was evaluated using the CellTiter-Glo cell viability assay reagent;

[0047] 4) Calculate the Log2 Fold Change (Log2FC) of the cell viability ratio between CuET treatment and control for each drug as the drug activity score.

[0048] (2) Data analysis and screening: Using Log2FC as an indicator, drugs with CuET-dependent enhanced activity were screened in ascending order of Log2FC;

[0049] (3) Experimental results:

[0050] Experimental results are as follows Figure 1 As shown,

[0051] 1) Screening revealed that osimertinib significantly reduced cell viability in the context of CuET treatment and had the lowest Log2FC among lung cancer treatment drugs;

[0052] 2) This suggests that CuET, as a copper death inducer, can significantly enhance the efficacy of osimertinib, which has a synergistic mechanism.

[0053] 2. Sensitivity screening of programmed cell death pathways revealed that osimertinib resistance indicates susceptibility to copper death.

[0054] (1) Activity-based programmed cell death sensitivity screening

[0055] 1) Wild-type and osimertinib-resistant lung adenocarcinoma HCC827 and H1975 cells were seeded into 96-well plates, respectively;

[0056] 2) Treat the cells with various cell death inducers, such as apoptosis inducers (cisplatin, etoposide) and ferroptosis inducers (RSL3, erastin);

[0057] 3) After 72 hours of treatment, cell viability was detected, response heatmaps were plotted, and the activity changes of different cells under treatment with inducers of various pathways were compared.

[0058] (2) Sensitivity screening based on programmed cell death markers

[0059] 1) Western blot was used to detect the expression levels of different markers of programmed cell death in cells, such as FDX1 (a key driver of copper death), GPX4 (a marker of ferroptosis), and GSDMD (a marker of pyroptosis).

[0060] 2) Simultaneously detect the expression of FDX1 in osimertinib-sensitive patient samples (patient-OS) and drug-resistant patient samples (patient-OR).

[0061] (3) Experimental results, such as Figure 2 As shown:

[0062] 1) Cell viability thermograms showed that osimertinib-resistant cells (HCC827OR, H1975OR) exhibited a specifically enhanced sensitivity to the copper death inducer CuET, while there was no significant change in the response to inducers of ferroptosis and pyroptosis pathways.

[0063] 2) Protein expression results showed that the expression of the copper death marker FDX1 was significantly increased in drug-resistant cells and patient-derived samples, while other death markers such as GPX4 and GSDMD showed no significant changes;

[0064] 3) The above results suggest that osimertinib-resistant cells or patients may have a potential susceptibility to copper death.

[0065] Example 2

[0066] Cellular level experiments

[0067] 1. Experimental materials:

[0068] 1) Osimertinib: Purchased from MedChemExpress (MCE);

[0069] 2) CuET (copper diethyl dithiocarbamate): copper death inducer, purchased from Tokyo Chemical Industry Co., Ltd. (TCI).

[0070] 3) Cell lines: HCC827 and H1975 were purchased from ATCC. The drug-resistant HCC827OR and H1975OR cells were induced using internationally accepted methods and tested by IC50 assay.

[0071] 4) Cell culture conditions: RPMI 1640 + 10% FBS + 1% penicillin and streptomycin, cultured at 37℃ and 5% CO2.

[0072] 2. Experimental Methods:

[0073] (1) Construction of drug-resistant cell lines

[0074] 1) After purchasing HCC827 and H1975, they were cultured in conventional Gbico 1640 medium, with medium changes and subcultured for 7 days until stable.

[0075] 2) After passage, maintain osimertinib concentration and gradually increase it to 10 μM for 1 month to induce osimertinib-resistant cell lines;

[0076] 3) Cell viability assays were performed to verify that the constructed HCC827OR and H1975OR cell lines were osimertinib-resistant cell lines.

[0077] (2) Group Design

[0078] 1) Negative control group: No drug treatment was given.

[0079] 2) Single-drug control group: treated with CuET (0.5 μM) or osimertinib (0.1 μM), respectively.

[0080] 3) Experimental group: CuET (0.5 μM) and osimertinib (0.1 μM) were added simultaneously for combined treatment.

[0081] (3) Three days after drug treatment, functional experiments were conducted to evaluate the efficacy of copper death-induced enhanced osimertinib. Cell viability assay (CCK8), colony formation assay, IncuCyte imaging real-time proliferation analysis and flow cytometry were used to analyze cell death patterns.

[0082] 3. Experimental results, such as Figure 3 As shown:

[0083] 1) CuET combined with osimertinib showed a significant synergistic effect on HCC827 OR cells:

[0084] Three-dimensional synergistic scoring analysis showed that CuET combined with osimertinib exhibited a significant synergistic inhibitory effect in HCC827 OR cells, with a mean synergistic score of 15.61, which was statistically significant (p = 8.51 e). -6 ).

[0085] 2) CuET combined with osimertinib significantly enhanced the sensitivity of drug-resistant lung cancer cells to osimertinib:

[0086] In HCC827 OR and H1975 OR cells, combined CuET treatment significantly improved cell sensitivity to osimertinib. Cell viability assays showed that cell viability decreased significantly in the CuET-treated group at multiple osimertinib concentration gradients, and the combination therapy group exhibited more significant cell growth inhibition compared to the monotherapy group (p<0.01), indicating that CuET helps reverse osimertinib resistance.

[0087] 3) CuET combined with osimertinib significantly inhibited the real-time proliferation of drug-resistant lung cancer cells:

[0088] Using the IncuCyte real-time proliferation monitoring system, it was observed that the combined treatment with CuET and osimertinib significantly inhibited the increase in relative cell coverage in both HCC827 OR and H1975 OR cells. Compared with the single-drug groups, the combination group showed a significant inhibitory effect on proliferation from 24 hours and lasted until 72 hours, with a statistically significant difference (p<0.01).

[0089] 4) CuET combined with osimertinib significantly reduced the clonogenic ability of drug-resistant lung cancer cells:

[0090] Colony formation assays showed that in HCC827 OR and H1975 OR cells, CuET or osimertinib alone could partially inhibit colony formation, but combined treatment almost completely inhibited colony formation, as evidenced by a significant reduction in colony number and a marked decrease in staining intensity. These results further validate the potential of CuET in enhancing the anti-resistance effect of osimertinib.

[0091] Example 3

[0092] Organoid level experiments

[0093] 1. Experimental materials:

[0094] 1) Osimertinib: Purchased from MedChemExpress (MCE);

[0095] 2) CuET (copper diethyl dithiocarbamate): copper death inducer, purchased from Tokyo Chemical Industry Co., Ltd. (TCI).

[0096] 3) Organoid source: derived from surgical tissue or pleural effusion specimens from patients with EGFR-mutant non-small cell lung cancer, divided into osimertinib-sensitive samples and osimertinib-resistant samples.

[0097] 4) Organoid culture system: Substrate gel culture system + complete organoid culture medium, cultured and maintained according to the standard modeling system for lung cancer organoids.

[0098] 2. Experimental Methods:

[0099] (1) Constructing an organoid model

[0100] 1) Collect tumor samples from EGFR-mutant NSCLC patients, isolate single cells and seed them into matrix gel to create three-dimensional tumor organoids;

[0101] 2) Based on the patients' medication history, the samples were divided into a "sensitive group" and a "resistant group";

[0102] 3) After culturing for 14 days until the organoids have stabilized, drug treatment experiments were conducted.

[0103] (2) Grouping

[0104] 1) Control group: No drugs were added;

[0105] 2) Single-drug groups: treated with CuET (0.5 μM) or osimertinib (0.1 μM), respectively;

[0106] 3) Experimental group: CuET (0.5 μM) and osimertinib (0.1 μM) were added simultaneously for combined treatment.

[0107] (3) Experimental detection indicators

[0108] 1) Assess organoid structural changes through morphological observation and imaging recording;

[0109] 2) Use cytotoxicity assays (such as CellTiter-Glo 3D) to assess survival rates, record and compare the relative activity of organoids in different groups.

[0110] 3. Experimental results, such as Figure 4 As shown:

[0111] In osimertinib-resistant organoids, the CuET-osimertinib combination therapy group showed significant antitumor effects, with significantly smaller organoid volume and decreased survival compared to the monotherapy group. This combination also further enhanced the efficacy of osimertinib in sensitive organoids, suggesting that CuET has a broad-spectrum sensitizing effect. The experimental results indicate that copper death inducers can enhance osimertinib sensitivity at the organoid level, supporting its preclinical application value.

[0112] Example 4

[0113] Animal-level experiments

[0114] 1. Experimental materials:

[0115] 1) Nude mice: 6 weeks old, BALB / c-nu, purchased from Beijing Huafukang Experimental Animal Center, SPF grade.

[0116] 2) Cell lines: Wild-type cell line HCC827 and the constructed osimertinib-resistant cell line HCC827OR were used;

[0117] 3) Medications: Osimertinib and CuET;

[0118] 4) Delivery method: Osimertinib is administered by gavage, while CuET is administered by intraperitoneal injection.

[0119] 2. Experimental Methods:

[0120] (1) Establishing xenograft tumor models

[0121] 1) Subcutaneously inject HCC827 and HCC827OR cell suspensions into the backs of nude mice (5 × 10⁶ cells per mouse). 6 (cells) to establish drug-resistant xenograft tumors;

[0122] 2) When the tumor volume reaches 80-100 mm 3 At time (V=(length×width2) / 2), patients were randomly assigned to groups for drug intervention.

[0123] (2) Grouping and processing methods

[0124] 1) Control group: Injected with an equal volume of solvent (PBS or DMSO dilution);

[0125] 2) Osimertinib group: 5 mg / kg administered by gavage daily;

[0126] 3) CuET group: 1.5 mg / kg was injected intraperitoneally every 2 days;

[0127] 4) Combination group: Osimertinib and CuET were administered simultaneously at the above dosage.

[0128] (3) Experimental period and evaluation indicators

[0129] 1) Duration of treatment: 14 days;

[0130] 2) Measure the tumor volume every 7 days using the formula V = (length × width 2) / 2;

[0131] 3) At the end of the experiment, the mice were sacrificed, and the tumors were weighed and preserved for histological analysis.

[0132] 3. Experimental results, such as Figure 5 As shown:

[0133] 1) Compared with the monotherapy group, CuET combined with osimertinib significantly inhibited tumor growth, and the tumor volume and terminal tumor weight were significantly reduced, with statistical differences (p<0.001); 2) The animals were in good condition, and no obvious toxicity or weight loss was observed, suggesting that the combination therapy has good safety; 3) This result further confirms the application potential of copper death inducers in overcoming osimertinib resistance at the in vivo level, and has important translational medicine value.

[0134] As can be seen from the above embodiments, the present invention, through testing on cell lines, osimertinib resistance models, patient-derived organoids, and mouse xenograft models, found that copper death induction can significantly enhance the antitumor effect of osimertinib, especially showing a significant synergistic effect in resistance models.

[0135] Compared with current mainstream treatment strategies for EGFR-TKI (such as osimertinib) resistance (including combination chemotherapy, targeted drug upgrades, etc.), the solution provided by this invention has the following significant advantages:

[0136] 1) Strong mechanism independence, overcoming EGFR pathway dependence: Copper death induces the aggregation of mitochondrial lipid-acylated proteins and the inactivation of iron-sulfur cluster proteins, triggering a collapse of protein homeostasis, which is a novel regulatory cell death mechanism. This mechanism does not depend on the EGFR pathway itself and can bypass common drug resistance barriers such as EGFR site mutations and AKT activation, achieving effective killing of drug-resistant cells.

[0137] 2) High specificity and significant synergistic sensitization effect: FDX1, a copper death-sensitive signal, is commonly upregulated in osimertinib-resistant cells, suggesting its potential sensitivity to copper death induction. The copper death inducer used in this invention can form a synergistic effect with osimertinib in this context, significantly reducing the IC50 value and enhancing cytotoxicity, which is superior to traditional apoptosis, necrosis or ferroptosis drugs.

[0138] 3) Excellent safety and scalability: Compared to various broad-spectrum chemotherapy or TKI upgrades, copper death inducers exhibit lower cytotoxicity to normal cells, strong bioselectivity, and a good safety window. Their mechanism of action also supports complementary combination therapy with chemotherapy, immunotherapy, or other novel pathway interventions, demonstrating significant potential for expanded applications.

[0139] In summary, this invention is superior to existing technologies for overcoming EGFR-TKI resistance in terms of overcoming drug resistance mechanisms, achieving therapeutic synergy, improving treatment safety, and multi-pathway combination potential, and has strong innovation and clinical application prospects.

[0140] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Application of copper death inducers in the preparation of drugs for treating osimertinib-resistant non-small cell lung cancer.

2. The application according to claim 1, characterized in that, The copper death inducer was used in combination with osimertinib.

3. The application according to claim 1 or 2, characterized in that, The copper death inducer includes copper diethyl dithiocarbamate (CuET).

4. The application according to claim 3, characterized in that, The dosage of copper diethyl dithiocarbamate (CuET) is 1–2 mg / kg / 2 days.

5. The application according to claim 3, characterized in that, The dosage of osimertinib is 4–6 mg / kg / day.

6. A combination therapy for treating non-small cell lung cancer or osimertinib-resistant non-small cell lung cancer, characterized in that, Including copper death inducers copper diethyl dithiocarbamate (CuET) and osimertinib.

7. The application of copper death inducers in the preparation of reagents for inhibiting the proliferation of non-small cell lung cancer cell lines, characterized in that, The copper death inducer includes copper diethyl dithiocarbamate (CuET).

8. The application according to claim 7, characterized in that, The non-small cell lung cancer cell lines include one or more of the following: HCC827, H1975, HCC827 OR, and H1975 OR cells.

9. The application according to claim 8, characterized in that, The concentration of copper diethyl dithiocarbamate (CuET) is 0.1–1 μM.

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