Use of polyphosphate in preparation of osimertinib-resistant non-small cell lung cancer sensitization treatment drugs

Abstract

This invention discloses the application of polyphosphates in the preparation of sensitizing drugs for osimertinib-resistant non-small cell lung cancer, belonging to the field of targeted sensitization technology. This invention is particularly applicable to the treatment of EGFR-mutant osimertinib-resistant non-small cell lung cancer, significantly enhancing the killing effect of osimertinib on resistant tumor cells. By using polyphosphates in combination with osimertinib, or by using polyphosphates alone as a sensitizer, osimertinib resistance can be improved, significantly enhancing the therapeutic effect. This invention demonstrates the potential of polyphosphates to inhibit the progression of PC9 OR cells in vitro and in vivo, clarifies the mechanism of action of polyphosphates on PC9 OR cells, and confirms that polyphosphates achieve their inhibitory effect on PC9 OR cells by regulating the expression of circPDE8A, providing a basis for using polyphosphates in the preparation of therapeutic drugs for PC9 OR cell-related diseases.

Description

Technical Field

[0001] This invention belongs to the field of targeted sensitization technology, specifically involving the application of polyphosphates in the preparation of sensitizing therapeutic drugs for osimertinib-resistant non-small cell lung cancer. Background Technology

[0002] Lung cancer is mostly caused by gene mutations, such as epidermal growth factor receptor (EGFR) mutations. Its main characteristics are the presence of exon 19 deletion (Del19) and exon 21L858R point mutation. Abnormal expression or mutation of EGFR will cause continuous activation of downstream signaling pathways, thereby leading to tumor development. It is also closely related to treatment resistance, so it is often used as a target in treatment.

[0003] Currently, targeted therapies against EGFR include small molecule tyrosine kinase inhibitors (TKIs) and EGFR-targeting monoclonal antibodies. EGFR-targeting antibodies are mainly used to treat advanced colorectal and head and neck cancers because their clinical benefits are minimal, and they are not used to treat non-small cell lung cancer. To date, three generations of EGFR-TKIs have been approved and widely used to treat advanced NSCLC. Osimertinib, as an irreversible third-generation EGFR-TKI, is recommended by domestic and international guidelines as the first-line targeted drug for patients with advanced NSCLC. Although targeted therapy and immunotherapy have made significant progress in the treatment of NSCLC in recent years, drug resistance remains one of the main challenges limiting their efficacy. The median progression-free survival (mPFS) for first-line osimertinib is approximately 18.9 months, and for second-line osimertinib it is approximately 10.1 months. Most patients experience disease progression within 1-2 years, and improvements in overall survival (OS) have reached a bottleneck. Furthermore, there is a lack of standardized treatment after disease progression, with chemotherapy being the primary first-line option. However, the objective response rate of chemotherapy is only 15%-30%, and the median progression-free survival (mPFS) is approximately 4-6 months, resulting in limited survival benefits. The development of drug resistance not only significantly reduces treatment effectiveness but also leads to poor patient prognosis, necessitating new treatment strategies to overcome this problem.

[0004] Circular RNAs (circRNAs) are non-coding RNAs that typically exhibit tissue- or cell-type-specific expression. Compared to linear RNAs, circRNAs are less susceptible to degradation by exogenous enzymes and exhibit greater stability. Increasing research indicates that circRNAs can function as oncogenes or tumor suppressor genes, closely related to the development and progression of various cancers. The main biological functions of circRNAs are sponge-like adsorption and competitive binding to miRNAs. circRNAs can selectively degrade miRNAs and indirectly regulate the expression of downstream target genes, playing a crucial regulatory role in tumorigenesis, development, and drug resistance formation, and hold promise as potential targets for reversing tumor drug resistance.

[0005] Polyphosphates (polyp) are biopolymers composed of orthophosphate subunits that participate in cell signal transduction, energy metabolism, apoptosis, and are major regulators of coagulation and inflammation. Studies have shown that polyp has potential anti-tumor effects; it can reduce the level of adenosine triphosphate in tumor cells, decreasing their resistance to X-ray irradiation and acting as a sensitizer to radiotherapy in lung cancer cells. Furthermore, it inhibits bFGF-induced proliferation, ERK / p38 MAPK activation, capillary-like formation in endothelial cells, and in vivo angiogenesis by blocking the binding of bFGF to its cell surface receptors, thereby inhibiting melanoma formation. However, to date, there are no reports on polyp reversing osimertinib resistance or enhancing the killing effect of osimertinib on drug-resistant NSCLC cells.

[0006] Given the crucial role of circRNAs in tumor drug resistance and the pleiotropic antitumor potential of polyp, this application explores the sensitizing effect and molecular mechanism of polyp on osimertinib-resistant NSCLC, aiming to provide new treatment strategies and drug options for overcoming osimertinib resistance. Summary of the Invention

[0007] Technical problem solved: To address the above-mentioned technical problem, this invention provides the application of polyphosphates in the preparation of sensitizing drugs for osimertinib-resistant non-small cell lung cancer. By using polyphosphates in combination with osimertinib, or by using polyphosphates alone as sensitizers, osimertinib resistance can be improved, significantly enhancing the therapeutic effect.

[0008] Technical solution: Application of polyphosphates in the preparation of sensitizing drugs for osimertinib-resistant non-small cell lung cancer.

[0009] A sensitizing therapy for osimertinib-resistant non-small cell lung cancer, comprising polyphosphate and pharmaceutically acceptable excipients.

[0010] Preferably, the drug is used to enhance the sensitivity of osimertinib to drug-resistant non-small cells, synergistically inhibit the biological function of drug-resistant tumor cells, and reverse the osimertinib resistance phenotype.

[0011] Preferably, the polyphosphate is used to downregulate the expression level of circPDE8A, release miR-513a-5p, thereby inhibiting the expression of the SLC7A11 gene, inducing ferroptosis in osimertinib-resistant cells, and ultimately achieving the osimertinib sensitization effect.

[0012] Furthermore, the mechanism of ferroptosis is the inhibition of the SLC7A11-GSH-GPX4 antioxidant axis, including: reducing the expression level of SLC7A11, decreasing intracellular glutathione content, inhibiting glutathione peroxidase 4 activity, or increasing intracellular free Fe. 2+ Levels and accumulation of lipid peroxidation products.

[0013] Preferably, the drug also includes osimertinib.

[0014] Preferably, the drug is an oral or non-oral dosage form, which can be administered concurrently or sequentially with osimertinib.

[0015] Preferably, the drug is a pharmaceutically permissible dosage form, such as an injection, powder, ointment, or transdermal patch.

[0016] Preferably, the drug is a tablet, capsule, powder, pill, granule, solution, suspension, syrup, suppository, inhaler, or spray.

[0017] Preferably, the excipients include one or more of the following: fillers, stabilizers, diluents, adjuvants, excipients, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers, and lubricants.

[0018] Beneficial effects: The core mechanism by which polyphosphate (polyp) in this invention sensitizes osimertinib-resistant NSCLC is the activation of the ferroptosis pathway regulated by the "circPDE8A / miR-513a-5p / SLC7A11" axis: In osimertinib-resistant NSCLC cells (PC9 OR), circPDE8A is abnormally highly expressed, competitively binding to miR-513a-5p through the sponge effect, preventing miR-513a-5p from inhibiting the downstream target gene SLC7A11, thus upregulating SLC7A11 expression; As a key molecule in the SLC7A11-GSH-GPX4 antioxidant axis, high expression of SLC7A11 can maintain intracellular GSH content and GPX4 activity, inhibiting ferroptosis, thereby allowing tumor cells to evade the killing effect of osimertinib and form a drug-resistant phenotype. Following polyp administration, circPDE8A expression was specifically downregulated in PC9 OR cells, relieving its inhibition of miR-513a-5p adsorption. Free miR-513a-5p further targeted and inhibited SLC7A11 expression. Decreased SLC7A11 expression impaired the SLC7A11-GSH-GPX4 antioxidant axis, leading to reduced intracellular GSH levels and GPX4 activity, while also increasing free Fe... 2+The accumulation of lipid peroxidation products ultimately induces ferroptosis in osimertinib-resistant tumor cells. Ferroptosis significantly enhances the killing effect of osimertinib on resistant tumor cells, achieving a sensitizing effect of polyp on osimertinib. When used in combination, the antitumor effect is superior to that of osimertinib alone.

[0019] Compared with the prior art, the present invention has the following beneficial effects: Precisely targeting the bottleneck of osimertinib resistance: For the first time, the sensitizing effect of polyp combined with osimertinib on osimertinib-resistant NSCLC has been clearly demonstrated, filling the gap in the field of polyp in the sensitization of tumor targeted therapy, providing a new treatment direction for osimertinib-resistant patients, and solving the clinical pain point of poor treatment effect after drug resistance; Innovative sensitization mechanism: The mechanism of ferroptosis regulation by the “circPDE8A / miR-513a-5p / SLC7A11” axis was revealed. It is different from the traditional chemotherapy sensitization or targeted drug combination mechanism. It reverses the drug resistance phenotype by regulating the circRNA-miRNA-target gene pathway, with high specificity and clear target. Significant synergistic effect: In vitro and in vivo experiments have confirmed that when polyp is used in combination with osimertinib, the inhibition rate of proliferation, migration and invasion of drug-resistant tumor cells and the in vivo tumor growth inhibition effect are significantly better than polyp or osimertinib alone. Moreover, polyp has a wide effective dosage range (1-10 mg / kg) and high safety. Safety and specificity advantages: Polyp can specifically induce ferroptosis in osimertinib-resistant NSCLC cells, has low toxicity to normal lung epithelial cells, and has been shown to have anti-tumor activity in colorectal cancer, melanoma and other cancers, with high potential for clinical translation. Flexible and diverse dosage forms: It can be prepared into various dosage forms such as oral and injectable, and can be administered simultaneously or sequentially with osimertinib, adapting to different clinical treatment scenarios and ensuring high patient compliance. Attached Figure Description

[0020] Figure 1 This is a diagram showing the CCK-8 results of PC9 OR cells after polyp treatment according to the present invention; Figure 2 This is a diagram showing the CCK-8 results of normal lung epithelial cells MLE-12 after polyp treatment according to the present invention. Figure 3 This is a diagram of cell colony formation according to the present invention, wherein the left diagram shows the colony formation results of PC9 OR after treatment with different concentrations of polyp, and the right diagram shows the statistical diagram of PC9 OR cell colony formation; Figure 4The image shows the wound healing results of the present invention. The left image shows the PC9 OR wound healing results after treatment with different concentrations of polyp at different times, and the right image is a statistical chart of PC9 OR wound healing. Figure 5 This is a diagram showing the cell migration and invasion results of the present invention. Figure 5 The top-middle image shows PC9 OR cells; the left image in the bottom image shows PC9 OR cell migration statistics; and the right image in the bottom image shows PC9 OR cell invasion statistics. Figure 6 This is a Western blot image of N-cad and Vimentin, migration and invasion-related proteins of the present invention. Figure 7 This is a concentration screening chart of the combined effects of polyp and osimertinib according to the present invention. Figure 7 The left image shows the combined effect of 90 μM polyp and 2.5 μM osimertinib; the middle image shows the combined effect of 90 μM polyp and 5 μM osimertinib; and the right image shows the combined effect of 90 μM polyp and 10 μM osimertinib. Figure 8 The diagram shows the cell clone formation of the combined drug therapy of the present invention. The left diagram shows the clone formation results of PC9 OR after using polyp, osimertinib alone and after combined treatment. The right diagram shows the statistical diagram of PC9 OR cell clone formation. Figure 9 The image shows the wound healing results of this invention. The left image shows the wound healing results at different times after using polyp alone, osimertinib, and combined treatment. The right image is a statistical chart of PC9 OR wound healing. Figure 10 This is a diagram showing the cell migration and invasion results of the present invention. Figure 10 The top-middle image shows PC9 OR cells after treatment with polyp, osimertinib alone, and in combination. The left image in the bottom image shows the PC9 OR cell migration statistics, and the right image shows the PC9 OR cell invasion statistics. Figure 11 This is a Western blot image of N-cad and Vimentin, migration and invasion-related proteins of the present invention. Figure 12 The images show mouse tumors in the control group, polyp treatment group, osimertinib treatment group, and mice treated with the combination of the two drugs. The top image is a schematic diagram of mouse tumors after treatment, and the left image in the bottom image is a statistical chart of mouse tumor volume, while the right image is a statistical chart of mouse tumor weight. Figure 13 This is a diagram showing the high-throughput sequencing results of this invention. Figure 13The left image shows a heatmap of differentially expressed circRNAs between the control group and the polyp-treated group; the right image shows a gene expression volcano diagram. Figure 14 This is a diagram showing the RT-qPCR results of differentially expressed circRNAs in this invention. Figure 14 The expression results of the top 5 known circRNAs in the PC9 OR and polyp treatment groups were shown in the figure. Figure 15 This is a schematic diagram of the structure of circPDE8A of the present invention; Figure 16 This is an agarose gel electrophoresis image of circPDE8A of the present invention; Figure 17 This is a stability test diagram for circPDE8A of the present invention. Figure 17 The left image in the middle is a digestion diagram of RNase R, and the right image is a digestion diagram of actinomycin D. Figure 18 This is a cellular localization diagram of circPDE8A of the present invention; Figure 19 This is the miRNA prediction map of the present invention. Figure 19 The left image in the middle is the intersection of online prediction results, and the right image is a schematic diagram of the binding sites of circPDE8A with miR-338-3p and miR-513a-5p. Figure 20 This is an RT-qPCR detection image of miR-338-3p and miR-513a-5p of the present invention. Figure 20 The left and right figures show the expression levels of miR-338-3p in the PC9 OR and polyp treatment groups, respectively, while the right figure shows the expression levels of miR-513a-5p in the PC9 OR and polyp treatment groups. Figure 21 This is the mRNA prediction diagram of the present invention. Figure 21 The top image shows the intersection of online prediction results, and the bottom image shows a schematic diagram of the binding sites of SLC7A11 and miR-513a-5p. Figure 22 This is a statistical graph of RT-qPCR detection of SLC7A11 of the present invention; Figure 23 Western blot images of SLC7A11 and GPX4 proteins after treatment with different concentrations of polyp according to the present invention. Figure 24 This invention relates to the effects of different concentrations of polyp on Fe in PC9 OR cells. 2+ Content detection chart; Figure 25This is a graph showing the ROS content in PC9 OR cells after treatment with different concentrations of polyp according to the present invention. Figure 26 This is a graph showing the detection of GSH content in PC9 OR cells after treatment with different concentrations of polyp according to the present invention. Figure 27 This is a CCK8 plot showing the survival rate of PC9 OR cells after polyp and Fer-1 treatment according to the present invention. Figure 28 Fe of the present invention 2+ And GSH test results, Figure 28 The middle left figure shows Fe after polyp and Fer-1 processing. 2+ Content statistics chart, the right figure shows the GSH content statistics after polyp and Fer-1 treatment. Detailed Implementation

[0021] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Example 1

[0022] The application of polyphosphate (polyp) in the preparation of a sensitizing therapy for osimertinib-resistant non-small cell lung cancer. The structural formula of polyp is shown in formula (I):

[0023] Equation (Ⅰ).

[0024] I. Experimental Materials and Setup: 1. Cell Culture: Lung cancer drug-resistant PC9 OR cells were provided by Professor Chen Cheng's research group (Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University) and cultured in RPMI 1640 medium. The medium was supplemented with 10% fetal bovine serum and penicillin / streptomycin (100 U / ml). Osimertinib was continuously administered to the PC-9 OR cell culture medium at a concentration of 1 μM to maintain drug resistance. All cells were cultured in a humidified incubator at 37℃ with 5% CO2.

[0025] 2. Nude Rats Rearing: Male BALB / c nude rats were housed in SPF-grade barrier environments using individually ventilated cages (IVCs), maintaining a temperature of 25°C, humidity of 50%, and a 12-hour light cycle. Feed and bedding were sterilized by high temperature / irradiation, and sterile drinking water was provided.

[0026] II. Experimental Methods: 1. Cell viability assay: 3000 cells were seeded into 96-well plates with 6 replicates. Cell viability was assessed using a CCK-8 assay kit.

[0027] 2. Colony formation assay: Cells were seeded at a density of 700 cells per well in 6-well plates or 350 cells per well in 12-well plates and treated with polyp for 48 hours. After treatment, the cells were washed with PBS to remove residual drug and then cultured in fresh 1640 medium. The medium was changed every 3 days for a total of 12 days. After incubation, cells were fixed with 4% paraformaldehyde for 30 minutes and stained with 1% crystal violet (Solarbio, China) for 15 minutes. Excess crystal violet was washed away with PBS, and the cells were air-dried. Images were acquired for each well under white light, and colony counting was performed using Imagej.

[0028] 3. Wound Healing Assay: Cells from each group were first seeded in 6-well plates. After 24 hours of culture, the cells reached 90% confluence and maintained intact morphology. Two vertical lines were drawn at the center of each well using the tip of a 200µL pipette. The cell surface was then rinsed multiple times with PBS to remove all floating cell debris. 2mL of complete culture medium containing 2% FBS was added to each well. The scratches were imaged under a microscope at 0 hours, and then observed and photographed at 24h and 48h. The scratch assay results were analyzed using ImageJ software.

[0029] 4. Transwell assay: Cells were digested, centrifuged, and analyzed at 2 × 10⁻⁶. 5 Cells were resuspended in 1640 medium at a concentration of 100 cells / mL, and then 200 μL of cell suspension was used for migration and invasion assays. For the invasion assay, the upper chamber was coated with a 1:5 diluted matrix gel before seeding the cells into the chambers, and subsequent steps were the same as for the migration assay. For migration, incubation was performed for 24 h, and for invasion, incubation was performed for 48 h. After incubation, the bottom of the chamber was fixed with 4% paraformaldehyde for 15 min, then stained with 0.1% crystal violet for 15 min. After wiping the cells in the upper chamber with a moistened cotton swab, cell migration and invasion were observed under a microscope.

[0030] 5. Protein Immunoblotting: Total protein was extracted from cultured lung cancer cells or tissues, washed twice with 1×PBS, and then fully lysed on ice using RIPA lysis buffer. Protein samples were separated by electrophoresis on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel, and the gel was transferred to an NC membrane. The transferred NC membrane was then blocked in 5% skim milk for 1 hour and incubated overnight at 4°C with the corresponding primary antibodies, including N-cad (HuaBIO, ET1607-37, 1:1000), E-cad (HuaBIO, M1405-3, 1:1000), Vimentin (92547, Abcam, 1:1000), SLC7A11 (HUABIO, A7C6, 1:1000), GPX4 (Selleck, F1580, 1:3000), and GAPDH (HUABIO, ET1601-4, 1:10000). Finally, the membrane was incubated with the corresponding secondary antibody for 1 h to obtain an image.

[0031] 6. Tumor-bearing experiment: 5×10 6 PC9 OR cells were suspended in 200 μL of PBS and injected subcutaneously into the back of 4-week-old nude mice. Tumors were allowed to develop at a size of approximately 100-150 mg / m³. 3 Mice were randomly divided into four groups and administered saline, polyp (5 mg / kg), or osimertinib (2.5 mg / kg) by gavage daily, respectively. Mouse weight and tumor volume were measured every two days. After 15 days of treatment, the mice were euthanized. Tumor tissue was removed from the mice, photographed, and weighed. The tumor tissue was then fixed in 4% paraformaldehyde or immediately frozen in liquid nitrogen. All experimental procedures involving mice were performed in accordance with guidelines approved by the Ethics Review Committee of Jiangsu Normal University.

[0032] 7. RT-qPCR Detection: Total RNA was extracted from PC9 OR cells using TRIzo according to the manufacturer's protocol. The extracted RNA (1.0 μg) was reverse transcribed into cDNA using a reverse transcription kit. Real-time PCR analysis was performed using SYBR Green. Relative mRNA expression levels were calculated using the 2-ΔΔCt method.

[0033] 8. Statistical Data: The statistical analyses used in this application include t-tests and Pearson correlation coefficients applied to the publicly available data. Data are expressed as mean ± standard deviation of mean (SD), * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0034] III. Experimental Results 1. Polyp inhibits the proliferation, migration, and invasion of lung cancer PC9 OR cells in vitro and in vivo: e.g. Figure 1As shown, polyp has an effect on lung cancer growth. Polyp effectively inhibits the proliferation of PC9 OR cells. After 24 hours of treatment with polyp, the IC50 of PC9 OR cells was 90.12 μM. Figure 2 As shown, compared with normal lung epithelial cells MLE-12, PC9 OR cells were more susceptible to the effects of polyp after 24 hours of treatment. Figure 3 As shown, in the clonogenic assay, polyp can significantly inhibit cell proliferation. Figure 4 , Figure 5 As shown, with increasing polyp concentration, the migration and invasion abilities of PC9 OR cells were significantly inhibited. Figure 6 As shown, the expression of migration and invasion-related proteins N-cadherin and Vimentin was downregulated. These data indicate that polyp significantly inhibits the survival, proliferation, migration, and invasion of PC9 OR cells, demonstrating that polyp has a certain killing effect on lung cancer cells in vitro. Figure 7-12 As shown, polyp has an inhibitory effect on subcutaneous tumors in mice, and its combined effect with osimertinib shows better therapeutic effect, indicating that polyp has an inhibitory effect on drug-resistant lung cancer cells in vivo.

[0035] 2. circRNAs participate in the regulation of polyps: such as Figure 13 As shown, high-throughput sequencing revealed that compared to the control group (PC9OR), a total of 268 genes were upregulated and 167 genes were downregulated in the polyp-treated group. Figure 14 As shown, circPDE8A was significantly upregulated in PC9 OR, and its expression was downregulated after polyp treatment. Figure 15 As shown, circPDE8A is formed by circularization of exons 15-19, and its circularization site was verified by Sanger sequencing. Figure 16 As shown, circPDE8A can only be amplified in cDNA using divergent primers. Figure 17 As shown, compared to linear PDE8A, circPDE8A is less easily digested or attenuated after being acted upon by RNase R and actinomycin D. Figure 18 As shown, circPDE8A is located in the cytoplasm. These data indicate that circPDE8A is a relatively stable circular RNA located in the cytoplasm, highly expressed in PC9 OR, and its expression can be reduced by polyp.

[0036] 3. Polyp regulates drug-resistant lung cancer cells through the "circPDE8A / miR-513a-5p / SLC7A11" pathway: e.g., Figure 19 As shown, miR-513-5p may be an miRNA that binds to circPDE8A. (As indicated...) Figure 20 As shown, miR-513a-5p is downregulated in PC9 OR. Figure 21 As shown, the online website predicts that SLC7A11 is a downstream target gene of miR-513a-5p. Figure 22 As shown, SLC7A11 expression was upregulated in the PC9 OR group and significantly downregulated after polyp treatment.

[0037] 4. Polyp induces ferroptosis in lung cancer cells: such as... Figure 23 As shown, polyp treatment reduced the expression of ferroptosis-related proteins GPX4 and SLC7A11. Figure 24 As shown, Fe in lung cancer cells of the polyp-treated group 2+ Ion levels were higher than in the control group. For example... Figure 25 and Figure 26 As shown, with increasing polyp concentration, ROS levels increase in a dose-dependent manner, while GSH levels decrease. Figure 27 As shown, the ferroptosis inhibitor (Fer-1) can also reverse polyp-induced cell death. For example... Figure 28 As shown, ferroptosis inhibitors can reverse polyp-induced Fe... 2+ Upregulation and downregulation of GSH. These data suggest that polyp can induce ferroptosis in lung cancer cells by inhibiting the SLC7A11-GSH-GPX4 axis.

Claims

1. Application of polyphosphates in the preparation of sensitizing drugs for osimertinib-resistant non-small cell lung cancer.

2. A sensitizing therapy for osimertinib-resistant non-small cell lung cancer, characterized in that, Includes the polyphosphate as described in claim 1 and pharmaceutically acceptable excipients.

3. The osimertinib-resistant non-small cell lung cancer sensitizing therapy according to claim 2, characterized in that, The drug is used to enhance the sensitivity of osimertinib to drug-resistant non-small cells, synergistically inhibit the biological function of drug-resistant tumor cells, and reverse the osimertinib resistance phenotype.

4. The osimertinib-resistant non-small cell lung cancer sensitizing therapy according to claim 2, characterized in that, The polyphosphate is used to downregulate the expression level of circPDE8A, release miR-513a-5p, thereby inhibiting the expression of SLC7A11 gene, inducing ferroptosis in osimertinib-resistant cells, and ultimately achieving the osimertinib sensitization effect.

5. A sensitizing therapy for osimertinib-resistant non-small cell lung cancer according to claim 4, characterized in that, The mechanism of ferroptosis involves inhibiting the SLC7A11-GSH-GPX4 antioxidant axis, including: reducing SLC7A11 expression levels, decreasing intracellular glutathione levels, inhibiting glutathione peroxidase 4 activity, or increasing intracellular free Fe. 2+ Levels and accumulation of lipid peroxidation products.

6. The osimertinib-resistant non-small cell lung cancer sensitizing therapy according to claim 2, characterized in that, The drugs mentioned also include osimertinib.

7. The osimertinib-resistant non-small cell lung cancer sensitizing therapy according to claim 2, characterized in that, The drug is available in oral or non-oral dosage form and can be administered concurrently with or sequentially with osimertinib.

8. A sensitizing agent for osimertinib-resistant non-small cell lung cancer according to claim 2, characterized in that, The drug is a pharmaceutically permissible dosage form, such as an injection, powder, ointment, or transdermal patch.

9. A sensitizing agent for osimertinib-resistant non-small cell lung cancer according to claim 2, characterized in that, The drug is in the form of tablets, capsules, powders, pills, granules, solutions, suspensions, syrups, suppositories, inhalers, or sprays.

10. A sensitizing agent for osimertinib-resistant non-small cell lung cancer according to claim 2, characterized in that, The excipients include one or more of the following: fillers, stabilizers, diluents, adjuvants, excipients, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers, and lubricants.

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