非小细胞肺癌奥希替尼耐药机制及应对策略的研究进展

The mechanism and response strategies of osimertinib resistance in non-small cell lung cancer

摘要:

随着对肺癌发病机制的深入研究，驱动基因指导下的分子靶向治疗在非小细胞肺癌治疗方面取得突 破性进展。针对表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂被推荐为EGFR突变阳性非小细胞肺癌的一线用 药。奥希替尼作为三代酪氨酸激酶抑制剂，其临床反应和效果显著优于一、二代。尽管奥希替尼用于一、二线非小 细胞肺癌治疗均取得了显著的成功，但其获得性耐药问题已成为亟待解决的临床瓶颈。本文综述了非小细胞肺癌 奥希替尼原发性［BIM（Bcl-2 interacting mediator of cell death）和磷酸酶与张力蛋白同源物（PTEN）缺失］及继发性 耐药机制（EGFR依赖性和非依赖性），同时针对不同耐药机制制定应对策略，包括奥希替尼联合其他药物治疗、变 构EGFR抑制剂和多靶点抑制剂等，以期为增强临床非小细胞肺癌靶向治疗的效果提供参考。

Abstract:

With the in-depth research on the pathogenesis of lung cancer, driver gene-guided molecular targeted therapy has made breakthrough progress in the treatment of non-small cell lung cancer. Tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) have been recommended as first-line agents for EGFR mutationpositive non-small cell lung cancer. As a third-generation tyrosine kinase inhibitor, osimertinib shows much better clinical response and efficacy than first- and second-generation tyrosine kinase inhibitors. Despite the remarkable success of osimertinib in both first- and second-line NSCLC treatment, the inevitable acquired resistance has become an urgent clinical issue. This article reviews the primary resistance mechanisms of osimertinib BIM(Bcl-2 interacting mediator of cell death) and PTEN (phosphatase and tensin homologue) deficiency and secondary resistance mechanisms (EGFRdependent and non-dependent resistance mechanisms) of osimertinib in non-small cell lung cancer, and the coping strategies formulated for it, including osimertinib combined with other drug treatments, allosteric EGFR inhibitors and multi-target inhibitors are used to provide a reference for enhancing the effect of targeted therapy for clinical non-small cell lung cancer.