Application of AKT inhibitor

Abstract

The invention discloses application of an AKT inhibitor, and the inhibitor is suitable for treating EGFR mutant non-small cell lung cancer or small cell lung cancer, can play a role by inhibiting EGFR kinase activity and down-regulating protein expression, and overcomes the drug resistance problem of existing EGFR targeted drugs. Within a small blood concentration range, cancer cells can be killed.

Description

Technical Field

[0001] This application relates to the application of an AKT inhibitor, specifically the application of an AKT inhibitor in the preparation of drugs for treating EGFR-mutant cancers, and belongs to the field of biomedical technology. Background Technology

[0002] Lung cancer is one of the leading causes of cancer-related deaths worldwide, with most patients diagnosed at an advanced stage, resulting in limited treatment options. Traditional platinum-based doublet chemotherapy and radiotherapy have generally poor efficacy, and the 5-year survival rate for advanced-stage patients is low. Advances in molecular genetics research have led to targeted therapy that has significantly improved the prognosis for some patients. However, acquired resistance is still difficult to avoid with targeted therapy, and most patients experience disease progression after the initial response.

[0003] In targeted therapy for lung cancer, EGFR, as an important receptor tyrosine kinase, can lead to persistent activation of downstream signaling pathways and treatment failure due to its abnormal activation. While EGFR-targeting tyrosine kinase inhibitors have shown some success in treating non-small cell lung cancer, their efficacy is often limited by acquired resistance. Resistance mechanisms include secondary mutations in the EGFR gene, activation of bypass signaling pathways, and abnormal activation of downstream signaling pathways, resulting in diminished efficacy of existing targeted drugs in long-term treatment and posing challenges to disease control.

[0004] AKT, or protein kinase B, is a serine / threonine protein kinase that plays a central role in regulating cell growth, metabolism, and survival. Abnormal activation of this pathway is closely related to the occurrence, development, and treatment resistance of various tumors. Although the AKT signaling pathway plays a crucial role in various malignant tumors, and several AKT inhibitors have entered clinical trials, the development of AKT inhibitors in lung cancer treatment still faces challenges such as high toxicity, insufficient biological activity, and the induction of increased AKT phosphorylation. Currently, there is a lack of highly effective and safe AKT inhibitors for the clinical treatment of lung cancer. Summary of the Invention

[0005] The purpose of this application is to overcome the shortcomings of the prior art and provide an application of AKT inhibitors to solve the problems of limited treatment options, easy development of drug resistance, and lack of highly efficient and selective targeted therapy for EGFR-mutant cancers.

[0006] To solve the above problems, the technical solution adopted in this application is: This application provides an application of an AKT inhibitor in the preparation of a drug for treating EGFR-mutant cancers.

[0007] In conjunction with the first aspect, the EGFR-mutant cancer is further described as a malignant epithelial tumor of the lung.

[0008] Furthermore, the malignant tumor of the lung epithelium is non-small cell lung cancer or small cell lung cancer.

[0009] Furthermore, EGFR mutations include any one or more of the following: exon 19 deletion, exon 21 L858R, exon 18 G719X, exon 21 L861Q, exon 20 ins A763_Y764insFQEA insertion mutation, compound mutation, exon 20 T790M, exon 20 insertion mutation, exon 20 S768I, and exon 20 C797S.

[0010] Furthermore, the drug comprises a therapeutically effective amount of the AKT inhibitor AZD5363, at a concentration of at least 0.1 μM.

[0011] Furthermore, the AKT inhibitor AZD5363 has a blood concentration of 0.1 μM to 10 μM in the patient.

[0012] Furthermore, the AZD5363 exerts its effects by inhibiting EGFR kinase activity and / or downregulating EGFR protein expression levels.

[0013] Furthermore, the drug comprises one or more pharmaceutically acceptable carriers or excipients.

[0014] Secondly, this application provides a pharmaceutical composition for treating EGFR-mutant lung cancer, comprising a therapeutically effective amount of the AKT inhibitor AZD5363 and a pharmaceutically acceptable carrier.

[0015] In conjunction with the second aspect, the dosage form of the pharmaceutical composition is an oral preparation, a lozenge, or an injection.

[0016] Compared with the prior art, the beneficial effects achieved by this application are as follows: This application utilizes the AKT inhibitor AZD5363 to prepare a drug for treating EGFR-mutant cancers. By leveraging the dual mechanism of action of AZD5363—inhibiting EGFR kinase activity and downregulating EGFR protein expression—it blocks the EGFR signaling pathway, enhances anti-tumor efficacy, and achieves effective treatment for EGFR inhibitor-resistant populations. This provides a novel alternative treatment option with a different mechanism of action for clinical practice.

[0017] By controlling the dosage of AZD5363 to achieve a blood concentration in patients ranging from 0.1 μM to 10 μM, a balance is struck between optimal selective killing of EGFR-mutant cancer cells and minimal off-target toxicity. Attached Figure Description

[0018] Figure 1The EGFR kinase activity of the small molecule AZD5363, which is the first sequenced to dock with the EGFR-19S-T790M configuration, and the positive reference EGFR inhibitor Osimertinib, provided in this application. Figure 2 The molecular docking results of AZD5363 and EGFR-T790M provided in this application show that AZD5363 can bind to the groove, and the amide bond of AZD5363 forms a hydrogen bond with Asn842; Figure 3 The growth status of lung cancer organoids provided in this application after 10 days of continuous culture; Figure 4 Histopathological analysis results of lung adenocarcinoma organoids and their original tumor tissue provided in this application; Figure 5 Histopathological analysis results of lung squamous cell carcinoma organoids and their original tumor tissues provided in this application; Figure 6 Histopathological analysis results of small cell lung cancer organoids and their original tumor tissues provided for this application; Figure 7 The results of drug sensitivity testing of 41 lung cancer organoids, including EGFR mutation-positive organoids, provided for this application to the AKT inhibitor AZD5363; Figure 8 Representative images provided in this application show the changes in EGFR expression levels in EGFR mutation-positive lung cancer organoids after treatment with the AKT inhibitor AZD5363 and the solvent control group for 7 days. Figure 9 Representative images illustrating the dose-dependent inhibitory effect of the AKT inhibitor AZD5363 provided in this application on organoids from EGFR-mutant colorectal cancer; Figure 10 The drug sensitivity curve of the AKT inhibitor AZD5363 provided in this application for organoids from EGFR-mutant colorectal cancer. Detailed Implementation

[0019] The present application will be further described below with reference to the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present application, and should not be used to limit the scope of protection of the present application.

[0020] When this application discloses a numerical range, the numerical range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed in this application should be understood to include any and all subranges to which they are included.

[0021] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. The terminology used in this application and in its specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used in this application includes any and all combinations of one or more of the associated listed items.

[0022] This application provides an application of an AKT inhibitor, specifically relating to the application of an AKT inhibitor AZD5363 in the preparation of a drug for treating EGFR-mutant lung cancer.

[0023] EGFR mutations include any one or more of the following: exon 19 deletion, exon 21 L858R, exon 18 G719X, exon 21 L861Q, exon 20 ins A763_Y764insFQEA insertion mutation, compound mutation, exon 20 T790M, exon 20 insertion mutation, exon 20 S768I, and exon 20 C797S.

[0024] The following detailed examples illustrate the application of the AKT inhibitor AZD5363 in enhancing drug sensitivity in EGFR-mutant lung cancer. Unless otherwise specified, all raw materials used in the following examples are commercially available products. The EGFR wild-type and mutant lung cancer organoids used in the following examples were obtained through clinical tissue culture in accordance with informed consent and ethical approval.

[0025] Example 1:

[0026] This embodiment studies the effect of the AKT inhibitor AZD5363 on EGFR kinase activity. The specific experimental steps are as follows: Small molecule sequencing was performed using the EGFR-19S-T790M configuration docking. A virtual screening was conducted on 6367 small molecules from the Huawei Pangu Drug Model and Drug Bank databases. The sequencing was integrated using the RANK PRODUCT method based on four sequencing methods: Vina affinity, CNN score, CNNaffinity, and pangu affinity. Finally, VX-702, Surufatinib, Lorecivivint, and AZD5363 were selected for subsequent EGFR kinase activity assays. Figure 1 As shown.

[0027] The EGFR kinase activity of AZD5363 and the positive reference EGFR inhibitor Osimertinib was detected by TR-FRET, a time-resolved fluorescence resonance energy transfer technique. The specific procedure is as follows: AZD5363 and the positive reference Osimertinib were dissolved in DMSO and serially diluted 3-fold to obtain 11 concentrations ranging from 1 μM to 0.056 nM. These were then added sequentially to 384-well plates with two replicates. Each plate included both a positive control well and a negative control well, with osimertinib as the positive control. Donor antibodies against phosphorylated EGFR WT type were added to each well to label the Eu chelate, and receptor antibodies labeled with the receptor fluorophore were added to bind the donor antibody. The plates were then incubated at room temperature for 1 h to allow for complete binding of the antibody to phosphorylated EGFR. Fluorescence signals were detected using a time-resolved fluorescence plate reader, measuring the intensity ratio of donor fluorescence at 615 nm to receptor fluorescence at 665 nm.

[0028] The experimental results were analyzed using XLFIT 5 software, and IC was calculated. 50 The result is as follows Figure 1 The IC of Osimertinib is shown. 50 The IC value of AZD5363 is 0.728. 50 The IC50 value was 0.0817, significantly better than the positive control EGFR inhibitors Osimertinib, VX 702, Surufatinib, and Lorecivivint. 50 A value greater than 1000 indicates that AZD5363 has the potential to be used as an anti-lung cancer drug.

[0029] Example 2:

[0030] In this embodiment, AZD5363 was selected to detect its molecular docking activity with EGFR T790M. Molecular docking and virtual high-throughput screening were performed using Discovery 833 Studio 2019 software, developed by Accelrys (DS2019 for short). Related graphs were generated using PyMOL software. The X-ray crystal structure of the EGFR-T790M complex, with PDB number 7jxl, was obtained from a protein database, and crystal water, disordered conformations, and ligands were removed.

[0031] Protein preparation: All incomplete residues and missing loops were optimized, and the protein was protonated at pH 7.4 using default parameters. The default parameters are generally as follows: Force field: CHARMM or similar, i.e., DS built-in force field.

[0032] pKa prediction: PROPKA algorithm or DS built-in equivalent algorithm.

[0033] Hydrogen atom addition: based on standard geometric rules and energy optimization.

[0034] Energy minimization: Local optimization, repairing only the affected area, avoiding overall conformational drift.

[0035] His protonation: Automatically selects HID (protonation at δ-nitrogen), HIE (protonation at ε-nitrogen), or HIP (diprotonation).

[0036] To ensure optimal coverage of the AZD5363 conformational space, the DS2019 docking algorithm LibDock was used in HighQuality mode for docking, and the BEST algorithm mode was used to generate conformations. Within this relative energy threshold of 10 kcal / mol, independent isomer conformations were formed. All other parameters were set to the program default values.

[0037] The results are as follows Figure 2 As shown, AZD5363 can bind to the EGFR-T790M groove, and the amide bond of AZD5363 forms a hydrogen bond with Asn842, demonstrating its inhibitory potential against clinically relevant EGFR mutants.

[0038] Example 3:

[0039] This embodiment studies the killing effect of the AKT inhibitor AZD5363 on organoids from EGFR mutation-positive lung cancer. The specific experimental steps are as follows: 3.1 Culture of lung cancer organoids; Fresh lung cancer tissue, approved by the ethics committee, was obtained. The lung cancer tissue samples were immersed in tissue preservation solution and transported to the laboratory within 2 hours at 4°C. Upon receipt, the samples were transferred to a laminar flow hood and washed three times with PBS containing 3% penicillin antibody (Gibco, catalog number 15140148). The samples were then minced to 1 mm using sterile surgical instruments. 3 After washing twice, the tissue pellet was digested in a 37°C water bath with a volume three times larger than the volume of the primary lung cancer tissue digestion solution (MLU0101, purchased from Ivylink Biotechnology Co., Ltd.). Microscopic observation was performed after digestion. The digestion was then terminated with a volume three times larger than the volume of the digestion solution in complete lung cancer organoid culture medium (MLU0101, purchased from Ivylink Biotechnology Co., Ltd.). Large tissue fragments were filtered through a 70 μm filter to remove them. The filtrate was collected, centrifuged to obtain the cell pellet, and resuspended in Matrigel (356231, purchased from Corning). 30 μL of the pellet was seeded into each well of a 24-well plate to form a dome-shaped structure. The plates were then incubated at 37°C with 5% CO2 for 20 min to allow the Matrigel to solidify.

[0040] After the matrix gel solidifies, add 500 μL of complete lung cancer organoid culture medium to each well. This culture medium was purchased from Ivy Biotechnology Co., Ltd., catalog number MLU0101-2. Change the medium every 3.5 days to maintain culture. Figure 3 As shown, the growth of these lung cancer organoids exhibits a temporal variation, and the morphology of the spherical organoids remains unchanged.

[0041] 3.2 Pathological consistency identification of lung cancer organoids and their original tumor tissues; When lung cancer organoids reach the passage criteria, they are collected for immunohistochemistry. Three to four wells are selected from each sample, and the organoids are broken up using pre-cooled 4% paraformaldehyde and collected into 2 mL EP. After complete fixation, they are embedded in paraffin and sectioned.

[0042] Sections were dewaxed by sequentially soaking in xylene, 95% ethanol, 80% ethanol, 70% ethanol, and distilled water for 10 min each, then soaked in citrate buffer and microwaved on medium heat for 15-25 min for antigen retrieval, followed by exposure to room temperature. Sections were treated with 0.2% Triton X-100 to allow antibodies to enter cells. Sections were then treated with 3% hydrogen peroxide methanol solution to remove endogenous peroxidase from the tissue, preventing interference with subsequent staining. Finally, sections were incubated with sheep serum to block non-specific binding sites.

[0043] The specific primary antibody was diluted and added dropwise to the slides, then incubated overnight at 4 °C to allow the antibody to specifically bind to the antigen. After incubation with the primary antibody, the slides were washed with PBS, and then HRP-labeled secondary antibody was added and incubated at room temperature for 1 h. After washing the slides with PBS, DAB chromogenic solution was used for staining for 10–30 s, and the staining was observed under a microscope. After staining, the reaction was terminated with distilled water, and the cell nuclei were stained with hematoxylin. After rinsing with running water, the slides were allowed to stand to revert to blue. Finally, the slides were dehydrated with a gradient of ethanol and xylene, mounted with neutral resin, and the staining results were observed under a microscope.

[0044] The primary antibodies used in this embodiment include: TTF-1, purchased from Abcam (catalog number ab227652); CK7, purchased from Abcam (catalog number ab68459); Napsin, purchased from Abcam (catalog number ab133249); CK5 / 6, purchased from Proteintech (catalog number 68295-1); P40, purchased from ABclonal (catalog number A4782); and P63, purchased from Abcam (catalog number ab124762). The results are as follows: Figure 4 , Figure 5 and Figure 6 As shown.

[0045] Figure 4 In the lung adenocarcinoma, organoids derived from lung adenocarcinoma cluster together, exhibiting subtle cytological features, producing acini or large gland-like structures, and retaining the expression of lung adenocarcinoma markers Napsin A, thyroid transcription factor 1 (TTF-1), and cytokeratin 7 (CK7).

[0046] Figure 5 In squamous cell carcinoma organoids, distinct cell boundaries and cytoplasmic keratinization are histological characteristics of squamous cell carcinoma tissues. They also highly express the characteristic markers of squamous cell carcinoma, P63 and CK5 / 6. Organoids derived from complex small cell lung cancer have small cell morphology, less periplasm, and express neuroendocrine markers such as CD56, synaptophysin Syn, CgA, and TTF-1. Figure 6 As shown.

[0047] The above figures show that the lung cancer organoids constructed in this application can maintain the morphological and pathological characteristics of the original tumor and reflect its individual characteristics.

[0048] 3.3 Detection of AZD5363's killing effect on lung cancer organoids; When lung cancer organoids reached the passage criteria, they were collected for drug sensitivity testing: Organoids were lysed with pre-cooled PBS and collected into 15 mL centrifuge tubes. After centrifugation, the supernatant and gel layer were discarded. 1 mL of TrypLE™ ExpressEnzyme was added, and the tubes were incubated in a 37 °C water bath with shaking for approximately 2–3 min. The digestive enzyme was purchased from Gibco (catalog number 12605010). After microscopic observation, digestion was terminated with 3 mL of PBS. Cell pellet was obtained after centrifugation and resuspended in Matrigel (catalog number 356231) from Corning.

[0049] 10 μL of the organoids were seeded into each well of a 96-well plate to form a dome-shaped structure, and the density of organoids per well was controlled to be about 2000. The plate was then placed in a cell culture incubator and incubated for 20 min to allow the matrix gel to solidify. The incubator conditions were 37 °C and 5% CO2.

[0050] After the matrix gel solidified, 100 μL of lung cancer organoid culture medium was added to each well, and the medium was changed periodically at 2-day intervals thereafter. The culture medium was purchased from Ivy Biotechnology Co., Ltd., catalog number MLU0101-2. Approximately 4 days after inoculation, when the organoids reached a size of about 50 μm, each lung cancer organoid was treated with 0, 0.1 μM, 2 μM, and 10 μM concentrations of AZD6363, and the inhibitory rate of AZD6363 on the activity of lung cancer organoids was measured. Each drug was tested in triplicate. The first administration was designated as Day 0. On Day 2 and Day 5, the culture medium in each well was replaced with fresh drug-containing medium at the corresponding concentration. On Day 7, the culture medium in each well was discarded, and CTG diluted 1:1 with the culture medium (CellTiter-Glo 3D CellViability Assay, purchased from Promega, catalog number G9681) was added. The microplates were incubated at room temperature on a shaker for 2 h, and then the luminescence values ​​were recorded using the chemiluminescence module of the microplate reader of an ELISA reader. The ELISA reader was a BioTek Synergy H1 model. The inhibition rate of AZD5363 on lung cancer organoid activity at concentrations of 0, 0.1 μM, 2 μM and 10 μM was calculated.

[0051] The results are as follows Figure 7 As shown, the AKT inhibitor AZD5363 exhibits significantly stronger cytotoxic effects on EGFR-mutant lung cancer organoids than on EGFR wild-type lung cancer organoids. In summary, this embodiment demonstrates that the AKT inhibitor AZD5363 can significantly enhance the drug sensitivity of EGFR-mutant lung cancer organoids, thereby achieving a therapeutic effect on EGFR-mutant lung cancer.

[0052] Example 4:

[0053] This embodiment studies the killing effect of the AKT inhibitor AZD5363 on organoids from EGFR mutation-positive lung cancer. The specific experimental steps are as follows: On day 7 after drug administration in the drug sensitivity test, the 96-well plate was removed, the culture supernatant was discarded, and the plate was washed with PBS. After washing with 4% paraformaldehyde at room temperature for 15 min, the plate was fixed. After washing three times with PBS, the plate was blocked with 3% BSA for 10 min. The BSA was purchased from BIOSHARE (product number BS114) and is used to block non-specific binding sites. 50 μL of anti-EGFR antibody diluted 1:200 with 5% BSA (product number ab52894) was added to each well. The plate was incubated overnight at 4 °C to allow the antibody to specifically bind to the antigen. After incubation with the primary antibody, the plate was washed three times with PBS. 50 μL of secondary antibody diluted 1:100 with PBS (product number AS053) was added to each well. The plate was incubated at room temperature for 1 h. After washing three times with PBS, a small amount of DAPI (product number P0131) was added to each well for nuclear staining. Then, a fluorescence microscope was used to take pictures and record the fluorescence intensity. The microscope was an Olympus IX83 model.

[0054] like Figure 8 As shown, AZD5363 significantly inhibited the expression of EGFR in lung cancer organoids, indicating that the AKT inhibitor AZD5363 can significantly enhance the drug sensitivity of EGFR-mutant lung cancer organoids, thereby achieving the effect of treating EGFR-mutant lung cancer.

[0055] Example 5:

[0056] This embodiment investigates the inhibitory effect of the AKT inhibitor AZD5363 on the expression level of EGFR in organoids from EGFR-mutant colorectal cancer. The specific experimental steps are as follows: When colorectal cancer organoids reach the passage criteria, the organoids are collected for drug sensitivity testing: the organoids are lysed using pre-cooled PBS and collected into 15 mL centrifuge tubes. After centrifugation, the supernatant and gel layer are discarded, and 1 mL of TrypLE™ Express Enzyme is added and the organoids are digested in a 37 ℃ water bath with shaking for about 2 to 3 minutes. The digestive enzyme was purchased from Gibco, catalog number 12605010.

[0057] After microscopic observation of digestion, digestion was terminated with 3 mL of PBS. Cell pellet was obtained after centrifugation and resuspended in Matrigel (Catalyst No. 356231, Corning). 10 μL of the pellet was seeded into each well of a 96-well plate to form a dome-shaped structure, with an organoid density of approximately 2000 cells per well. The plates were then incubated for 20 min at 37 °C and 5% CO2 to allow the Matrigel to solidify.

[0058] After the matrix gel solidified, 100 μL of colorectal cancer organoid culture medium (purchased from Ivy Biotechnology Co., Ltd., catalog number MCU0101) was added to each well, and the medium was subsequently changed periodically at 2-day intervals. Three days after inoculation, when the organoids grew to approximately 50 μm, each colorectal cancer organoid was treated with AZD6363 at concentrations of 0, 0.0008 μM, 0.004 μM, 0.02 μM, 0.1 μM, 0.5 μM, 2.5 μM, 12.5 μM, 62.5 μM, and 321.5 μM to detect the inhibitory rate of AZD6363 on the activity of lung cancer organoids. Three replicate wells were set up for each drug. The first administration was designated as Day 0, and the medium in each well was replaced with fresh drug-containing medium at the corresponding concentration on Day 2 and Day 5. On day 7, the culture medium in each well was discarded, and CTG diluted 1:1 with the culture medium (CellTiter-Glo 3D Cell Viability Assay, purchased from Promega, catalog number G9681) was added. The wells were incubated at room temperature on a shaker for 2 hours. The luminescence values ​​were then recorded using the chemiluminescence module of a microplate reader (BioTek Synergy H1 model). The IC50 of the tumor-killing effect of AZD5363 was calculated. 50 .

[0059] The results are as follows Figure 9 As shown, AZD5363 inhibited the growth of organoids of EGFR-mutant colorectal cancer in a dose-dependent manner, and the necrotic core area of ​​organoids of EGFR-mutant colorectal cancer became larger with increasing dose.

[0060] like Figure 10 As shown, AZD5363 exhibits significant killing effect on organoids from colorectal cancer with EGFR mutations, with an IC50 value of [missing information]. 50 The concentration was 23.94 μM. In summary, this embodiment demonstrates that the AKT inhibitor AZD5363 can significantly enhance the drug sensitivity of organoids from EGFR-mutant colorectal cancer, thereby achieving a therapeutic effect on EGFR-mutant colorectal cancer.

[0061] It should be noted that, based on the verification results of the embodiments of this application, it can be seen that, based on the same mechanism of action, the AKT inhibitor AZD5363 of this application can also achieve the same therapeutic effect for other EGFR-mutant cancers, such as EGFR-mutant clear cell ovarian carcinoma, EGFR-mutant endometrioid ovarian carcinoma, EGFR-mutant gastric cancer, EGFR-mutant colon cancer, EGFR-mutant pancreatic cancer, EGFR-mutant melanoma, EGFR-mutant liver cancer, and EGFR-mutant bladder cancer.

[0062] Alternatively, this application also provides a pharmaceutical composition for treating EGFR-mutant lung cancer, comprising a therapeutically effective amount of the AKT inhibitor AZD5363 and a pharmaceutically acceptable carrier. The pharmaceutical composition may be in the form of an oral formulation, a tablet, or an injection.

[0063] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. An application of an AKT inhibitor, characterized in that, The application of the AKT inhibitor in the preparation of drugs for treating EGFR-mutant cancers.

2. The application according to claim 1, characterized in that, The EGFR-mutated cancer is a malignant tumor of the lung epithelium.

3. The application according to claim 2, characterized in that, The malignant epithelial tumor of the lung is either non-small cell lung cancer or small cell lung cancer.

4. The application according to claim 1, characterized in that, EGFR mutations include any one or more of the following: exon 19 deletion, exon 21 L858R, exon 18 G719X, exon 21 L861Q, exon 20 ins A763_Y764insFQEA insertion mutation, compound mutation, exon 20 T790M, exon 20 insertion mutation, exon 20 S768I, and exon 20 C797S.

5. The application according to claim 1, characterized in that, The drug includes a therapeutically effective amount of the AKT inhibitor AZD5363 at a concentration of at least 0.1 μM.

6. The application according to claim 5, characterized in that, The AKT inhibitor AZD5363 was administered at blood concentrations ranging from 0.1 μM to 10 μM in patients.

7. The application according to claim 5, characterized in that, The AZD5363 works by inhibiting EGFR kinase activity and / or downregulating EGFR protein expression levels.

8. The application according to claim 1, characterized in that, The drug comprises one or more pharmaceutically acceptable carriers or excipients.

9. A pharmaceutical composition for treating EGFR-mutant lung cancer, characterized in that, It contains a therapeutically effective amount of the AKT inhibitor AZD5363 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that, The dosage form of the pharmaceutical composition is an oral preparation, a lozenge, or an injection.

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