奥希替尼在非小细胞肺癌靶向治疗中的获得性耐药机制

Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFRTKI)在治疗癌症的同时仍面临不可避免的耐药。通过研究EGFR-TKI发生耐药的机制从而发现一些新的分子标志物和药物靶点,促进了第三代TKIs的发展并针对耐药提出合理化建议。经临床验证,T790M是一个可用于判断预后的生物学标志物,可导致第一代和第二代TKIs的难治性。对于T790M阴性的患者,尽管靶向治疗和检查点阻断治疗结合可能提供有希望的替代方案,细胞毒性药物序贯EGFR-TKI治疗仍是疾病进展后可接受的标准治疗方式。在T790M阳性患者中,第三代EGFR-TKI药物奥希替尼在随机临床试验中优于铂类二联化疗和第一代EGFR-TKI。文章综述了近年来有关奥希替尼在非小细胞肺癌患者获得性耐药机制及治疗的主要文献,并展望了未来可能的研究方向。

While treating cancer,epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)still faces inevitable drug resistance.Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets,and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations.The threonine-to-methionine substitution mutation at position 790(T790M)is clinically validated to engender refractoriness to first-and second-generation TKI,and is a standard-of-care predictive biomarker used in therapeutic stratification.For patients who are T790M-negative,cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression,although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future.Among T790M-positive patients,the third-generation EGFR-TKI,osimertinib,has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials.This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs,and envisions future directions in translational and clinical research.