非小细胞肺癌EGFR-TKI治疗获得性耐药进化机制的研究

EGFR-TKI resistance is an important problem to be solved in the field of non-small cell lung cancer. At present, it is mainly through the discovery of new drug-resistant mutations, and the drug resistance problem cannot be solved fundamentally. We found that drug-resistant cells that evolved from drug-tolerant cells retained epigenetic characteristics under drug tolerance, showed APOBEC characteristic mutation profiles, and increased expression of IFNα, dsDNA, and STING, suggesting that EGFR-TKI leads to tumors. Death releases dsDNA, activates the STING/TBK1/IRF3/IFN pathway to increase IFN, and IFN promotes increased APOBEC expression. This study will use drug-resistant cell lines, model animals, patient specimens, using biochemistry, molecular biology, molecular genetics and other methods to confirm the above assumptions at multiple levels. To elucidate the evolutionary mechanism of EGFR-TKI acquired resistance, explore the key role of APOBEC in the evolution of drug-tolerant cells into drug-resistant cells, identify and interfere with drug-tolerant cells that occur during EGFR-TKI treatment. This study will reveal the mechanism of EGFR-TKI acquired evolutionary resistance, provide a theoretical basis for clinical delay or prevent the occurrence of drug resistance and find a drug target.

EGFR-TKI耐药是非小细胞肺癌领域亟待解决的重要问题，目前主要通过发现新的耐药突变加以干预，不能从根本解决耐药问题。我们发现从药物耐受细胞进化而来的耐药细胞保留了药物耐受状态下的表观遗传特征，表现出APOBEC特征突变谱，同时IFNα、dsDNA和STING表达升高，推测EGFR-TKI导致肿瘤死亡释放dsDNA，激活STING/TBK1/IRF3/IFN通路使IFN升高，IFN促使APOBEC表达增加。本研究将应用耐药细胞系、模式动物、患者标本，采用生物化学、分子生物学、分子遗传学等多种方法，多水平证实上述假设。阐明EGFR-TKI获得性耐药的进化机制，探索APOBEC在药物耐受细胞进化为耐药细胞过程中的关键作用，鉴别EGFR-TKI治疗时出现的药物耐受细胞并加以干预。本研究将揭示EGFR-TKI获得性进化耐药的机制，为临床延缓或阻止耐药的发生提供理论基础和寻找药物作用靶点。

EGFR-TKI耐药是非小细胞肺癌领域亟待解决的重要问题，目前主要通过发现新的耐药突变加以干预，不能从根本解决耐药问题。本研究应用耐药细胞系、模式动物、患者标本，采用生物化学、分子生物学、分子遗传学等多种方法，从研究药物耐受细胞进化成为耐药细胞的过程，聚焦药物耐受状态表现出的APOBEC特征突变谱，IFNα、dsDNA和STING等关键分子和通路。阐明EGFR-TKI导致肿瘤死亡释放dsDNA，激活STING/TBK1/IRF3/IFN通路使IFN升高，IFN促使APOBEC表达增加促进耐药的机制。本研究有助于揭示EGFR-TKI获得性进化耐药的机制，为临床延缓或阻止耐药的发生提供理论基础和寻找药物作用靶点。