Application of combination of osimertinib and chidamide in treatment of osimertinib drug-resistant lung cancer

Abstract

The invention discloses an application of osimertinib combined with chidamide in treatment of osimertinib drug-resistant lung cancer, and particularly relates to the following aspects: (1) osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and shows a remarkable curative effect in treatment of non-small cell lung cancer (NSCLC) patients carrying specific EGFR mutation; (2) chidamide is a novel oral HDACi, can induce cell apoptosis, cell cycle arrest and cell growth inhibition, and shows good tolerance and antitumor activity in various cancer types; and (3) chidamide is taken as an epigenetic regulating agent and can be in synergistic effect with osimertinib, so that the capability of killing lung cancer cells is enhanced. The invention belongs to the technical field of medicines, and particularly provides application of osimertinib combined with chidamide in treatment of osimertinib drug-resistant lung cancer.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer. Background Art

[0002] Lung cancer, also known as primary bronchial cancer or primary bronchial lung cancer, is the most common primary lung malignant tumor originating from the bronchial mucosa or glands. According to tissue lesions, it can be divided into small cell carcinoma and non-small cell carcinoma. Non-small cell lung cancer (NSCLC) is the most common, accounting for about 85% of the total incidence of lung cancer. Clinical symptoms are mostly hidden, mainly manifested as cough, sputum, hemoptysis and weight loss. Lung cancer is one of the malignant tumors with the highest morbidity and mortality worldwide.

[0003] Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has shown significant efficacy in the treatment of non-small cell lung cancer (NSCLC) patients carrying specific EGFR mutations. However, as the treatment duration increases, patients often develop resistance to osimertinib, leading to treatment failure.

[0004] Histone deacetylase inhibitors (HDACi) are a new class of anticancer drugs that have attracted much attention in recent years. They can regulate cellular responses by changing gene expression, inhibiting cell growth, inducing cell cycle arrest and apoptosis. Chidamide is a new oral HDACi that can induce apoptosis, cell cycle arrest and cell growth inhibition, and shows good tolerability and anti-tumor activity in various cancer types. Currently, there is a lack of effective treatments for patients with osimertinib-resistant lung cancer. Therefore, the development of new therapeutic strategies to overcome osimertinib resistance is an urgent need in the current field of lung cancer treatment.

[0005] The inventors of the present invention have studied a treatment method to overcome the resistance to osimertinib in response to the problem of osimertinib resistance. Compared with the prior art, the combination of osimertinib and cedabenb provides a new treatment option for patients with resistant lung cancer. Secondly, cedabenb has a unique mechanism of action that can inhibit the proliferation and metastasis of tumor cells and activate the immune response mechanism of T cells to resist malignant cells. Compared with other combination regimens, this regimen may have better efficacy and safety. For example, in the existing combination regimen, the objective response rate of osimertinib combined with savotinib is 49% in resistant patients with high levels of MET expression; while the combination of osimertinib and cedabenb can improve the efficacy, inhibit the growth and spread of tumor cells, have a higher response rate, prolong the survival of patients, and at the same time, reduce adverse reactions and bring greater clinical benefits to patients. Summary of the invention

[0006] In view of the above situation, in order to make up for the above existing defects, the present invention provides the use of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer.

[0007] The present invention provides the following technical solution: The application of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer proposed in the present invention is specifically in the following aspects:

[0008] (1) Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has shown significant efficacy in the treatment of non-small cell lung cancer (NSCLC) patients carrying specific EGFR mutations;

[0009] (2) Chidamide is a novel oral HDACi that can induce apoptosis, cell cycle arrest, and cell growth inhibition, and shows good tolerability and anti-tumor activity in multiple cancer types;

[0010] (3) As an epigenetic regulator, cedabendine can synergize with osimertinib to enhance its ability to kill lung cancer cells;

[0011] (4) The combined use of osimertinib and cedabenbine can more effectively control the progression of lung cancer and prolong the patient's progression-free survival. After receiving combined treatment, the time of disease progression was significantly delayed, providing patients with a longer stable treatment period;

[0012] (5) The combined use of osimertinib and chidamide can reduce the dosage of osimertinib and chidamide while ensuring the therapeutic effect;

[0013] (6) The combined use of osimertinib and cedabenbine can alleviate each other's toxic side effects to a certain extent;

[0014] (7) The combination of osimertinib and cedabenb has a certain therapeutic effect on osimertinib-resistant lung cancer patients with different resistance mechanisms;

[0015] (8) The combination therapy of osimertinib and cedabenb can be administered by conventional routes such as oral administration and injection, which is convenient for clinical application;

[0016] (9) The combination therapy of osimertinib and cedabenb can be combined with other lung cancer treatments (such as chemotherapy, radiotherapy, immunotherapy, etc.) to improve the comprehensive treatment effect.

[0017] Furthermore, the application of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer was verified by the following steps:

[0018] 1. Experimental Materials and Reagents

[0019] (1) Cell lines: PC9, PC9 / OR, H1975, H1975 / OR;

[0020] (2) Drugs: osimertinib, cedabenb;

[0021] (3) Reagents: RPMI1640 cell culture medium, fetal bovine serum, trypsin, WST-1, etc.;

[0022] 2. Experimental Methods

[0023] (1) Cell culture: Osimertinib-resistant lung cancer cell lines were cultured in a cell culture medium containing 10% fetal bovine serum in a 37° C., 5% CO 2 incubator;

[0024] (2) Drug treatment: The cells were divided into a control group, an osimertinib group, a chidamide group, and a combined treatment group. In different cell lines, the control group was given an equal volume of solvent, the osimertinib group was given different concentrations of osimertinib, the chidamide group was given different concentrations of chidamide, and the combined treatment group was given different concentrations of osimertinib and chidamide combined treatment;

[0025] (3) Cell proliferation detection: WST-1 was used to detect cell proliferation;

[0026] (4) Cell apoptosis detection: Annexin V-FITC / PI double staining method was used to detect cell apoptosis;

[0027] (5) Cell proliferation ability detection: Transwell was used to detect cell migration ability.

[0028] The beneficial effects achieved by the present invention using the above structure are as follows: The application of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer proposed by the present invention is specifically embodied in:

[0029] 1) Significantly improve the therapeutic effect: overcome drug resistance: The present invention effectively overcomes the drug resistance of lung cancer patients to osimertinib by combining osimertinib with cedabenib. Clinical research data show that compared with the use of osimertinib alone, the combined treatment regimen significantly improves the treatment efficiency and significantly increases the tumor reduction ratio; Enhance anti-tumor activity: cedabenib, as an epigenetic regulator, can synergize with osimertinib to enhance the killing ability of lung cancer cells. Combined therapy can act on multiple targets at the same time, inhibit the growth, proliferation and metastasis of tumor cells, and improve the overall anti-tumor activity.

[0030] 2) Prolong patient survival: Control disease progression: The combined treatment regimen can more effectively control the progression of lung cancer and prolong the patient's progression-free survival. After receiving combined treatment, the time of disease progression was significantly delayed, providing patients with a longer stable treatment period; Improve survival rate: Long-term follow-up results show that the combination of osimertinib and cedabenbine significantly improved the overall survival rate of lung cancer patients. The quality of life of patients has been improved, bringing new hope to lung cancer patients.

[0031] 3) Reduce toxic side effects: Reduce the dose of a single drug: Combination therapy can reduce the dose of osimertinib and cedamide while ensuring the therapeutic effect. This helps to reduce the toxic side effects of the drugs and reduce the incidence of adverse reactions caused by treatment in patients; Synergistic effect reduces toxicity: The combined use of osimertinib and cedamide can reduce each other's toxic side effects to a certain extent. For example, cedamide may reduce the adverse reactions such as rash and diarrhea caused by osimertinib, while osimertinib may also reduce the hematological toxicity of cedamide.

[0032] 4) Wide application scope: Applicable to patients with multiple drug resistance mechanisms: The combined treatment regimen of the present invention has a certain effect on osimertinib-resistant lung cancer patients with different drug resistance mechanisms. Whether the resistance is caused by EGFR gene mutation, bypass activation or other drug resistance mechanisms, the combined treatment may bring therapeutic benefits to patients; patients with different lung cancer subtypes benefit: This combined treatment regimen is not only suitable for patients with non-small cell lung cancer, but may also have potential therapeutic value for patients with other lung cancer subtypes. This provides a new treatment option for the majority of lung cancer patients.

[0033] 5) Convenient clinical application: Simple dosing regimen: The combined treatment regimen of osimertinib and cedamide can be administered orally and by injection, which is convenient for clinical application. Patients do not need to perform complex treatment operations, which improves treatment compliance; Good compatibility with existing treatment regimens: The combined treatment regimen of the present invention can be combined with other lung cancer treatment methods (such as chemotherapy, radiotherapy, immunotherapy, etc.) to improve the comprehensive treatment effect. At the same time, it has good compatibility with existing treatment regimens, which is convenient for clinicians to perform individualized treatment according to the specific conditions of the patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0035] Figure 1 This is a diagram showing the validation results that SRSF3 knockdown enhanced osimertinib sensitivity and reduced osimertinib resistance in osimertinib-resistant LUAD cells;

[0036] Figure 2 The figure shows the validation results of the anti-tumor effects of OSi and CHi alone or in combination on sensitive and resistant cells;

[0037] Figure 3 This is a diagram showing the validation results of the gene expression differences between PC9 and PC9 / OR cells;

[0038] Figure 4 The figure shows the validation results of the anti-tumor effects of Osi and CHi alone or in combination in osimertinib-resistant xenografts. DETAILED DESCRIPTION

[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0040] It should be noted that the words "front", "rear", "left", "right", "up" and "down" used in the following description refer to directions in the drawings, and the words "inside" and "outside" refer to directions toward or away from the geometric center of a specific component, respectively.

[0041] In order to study the application effect of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer, this example provides specific research methods and research results:

[0042] 1. Materials and Methods

[0043] 1. Experimental Materials and Reagents

[0044] (1) Cell lines: PC9, PC9 / OR, H1975, H1975 / OR;

[0045] (2) Drugs: osimertinib, cedabenb;

[0046] (3) Reagents: RPMI1640 cell culture medium (purchased from GIBCO), fetal bovine serum (purchased from GIBCO), trypsin, WST-1, etc.;

[0047] 2. Experimental Methods

[0048] (1) Cell culture: Osimertinib-resistant lung cancer cell lines were cultured in a cell culture medium containing 10% fetal bovine serum in a 37° C., 5% CO 2 incubator;

[0049] (2) Drug treatment: The cells were divided into a control group, an osimertinib group, a chidamide group, and a combined treatment group. In different cell lines, the control group was given an equal volume of solvent, the osimertinib group was given different concentrations of osimertinib, the chidamide group was given different concentrations of chidamide, and the combined treatment group was given different concentrations of osimertinib and chidamide combined treatment;

[0050] (3) Cell proliferation detection: WST-1 was used to detect cell proliferation;

[0051] (4) Cell apoptosis detection: Annexin V-FITC / PI double staining method was used to detect cell apoptosis;

[0052] (5) Cell proliferation ability detection: Transwell was used to detect cell migration ability.

[0053] 2. Experimental Results

[0054] (1) The IC50 test results showed that the IC50 of the osimertinib and chidamide combination treatment group was lower than that of the single-drug treatment group;

[0055] (2) The results of cell proliferation assays showed that both osimertinib and cedabenb alone could inhibit the growth of osimertinib-resistant lung cancer cells, and the inhibitory effect of the combined treatment group was more significant;

[0056] (3) The results of cell apoptosis detection showed that both osimertinib and cedabenb alone could induce apoptosis in osimertinib-resistant lung cancer cells, while the apoptosis rate in the combination treatment group was higher;

[0057] (4) Transwell assay results showed that both osimertinib and cedabenb alone could inhibit the migration ability of osimertinib-resistant lung cancer cells, while the migration ability of the combined treatment group was weaker;

[0058] (5) The results of in vivo animal subcutaneous tumor formation showed that both osimertinib and cedabenb alone could inhibit the growth of osimertinib-resistant lung cancer cells, and the inhibitory effect of the combination treatment group was more significant;

[0059] Therefore, the combination of osimertinib and chidamide is more effective than monotherapy with osimertinib or chidamide.

[0060] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, material or apparatus including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, material or apparatus.

[0061] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Use of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer, characterized in that: Specifically, it lies in the following aspects: (1) Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has shown significant efficacy in the treatment of non-small cell lung cancer (NSCLC) patients carrying specific EGFR mutations; (2) Chidamide is a novel oral HDACi that can induce apoptosis, cell cycle arrest, and cell growth inhibition, and shows good tolerability and anti-tumor activity in multiple cancer types; (3) As an epigenetic regulator, cedabendine can synergize with osimertinib to enhance its ability to kill lung cancer cells; (4) The combined use of osimertinib and cedabenbine can more effectively control the progression of lung cancer and prolong the patient's progression-free survival. After receiving combined treatment, the time of disease progression was significantly delayed, providing patients with a longer stable treatment period; (5) The combined use of osimertinib and chidamide can reduce the dosage of osimertinib and chidamide while ensuring the therapeutic effect; (6) The combined use of osimertinib and cedabenbine can alleviate each other's toxic side effects to a certain extent; (7) The combination of osimertinib and cedabenb has a certain therapeutic effect on osimertinib-resistant lung cancer patients with different resistance mechanisms; (8) The combination therapy of osimertinib and cedabenb can be administered by conventional routes such as oral administration and injection, which is convenient for clinical application; (9) The combination therapy of osimertinib and cedabenb can be combined with other lung cancer treatments (such as chemotherapy, radiotherapy, immunotherapy, etc.) to improve the comprehensive treatment effect.

2. The use of osimertinib combined with chidamide in the treatment of osimertinib-resistant lung cancer according to claim 1, characterized in that: Verify through the following steps: (1) Experimental materials and reagents 1) Cell lines: PC9, PC9 / OR, H1975, H1975 / OR; 2) Drugs: osimertinib, cedabenb; 3) Reagents: RPMI1640 cell culture medium, fetal bovine serum, trypsin, WST-1, etc.; (2) Experimental methods 1) Cell culture: The osimertinib-resistant lung cancer cell line was cultured in a cell culture medium containing 10% fetal bovine serum in a 37° C., 5% CO 2 incubator; 2) Drug treatment: The cells were divided into control group, osimertinib group, chidamide group and combined treatment group. In different cell lines, the control group was given an equal volume of solvent, the osimertinib group was given different concentrations of osimertinib, the chidamide group was given different concentrations of chidamide, and the combined treatment group was given different concentrations of osimertinib and chidamide combined treatment; 3) Cell proliferation detection: WST-1 was used to detect cell proliferation; 4) Cell apoptosis detection: Annexin V-FITC / PI double staining method was used to detect cell apoptosis; 5) Cell proliferation ability detection: Transwell was used to detect cell migration ability.

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