Tian Xueli, Gu Tingxuan, Lee Mee-Hyun, Dong Zigang
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China.
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China; College of Korean Medicine, Dongshin University, Naju, Jeonnam 582 45, Republic of Korea.
Biochim Biophys Acta Rev Cancer. 2022 Jan;1877(1):188645. doi: 10.1016/j.bbcan.2021.188645. Epub 2021 Nov 15.
Lung cancer causes the highest mortality compared to other cancers in the world according to the latest WHO reports. Non-small cell lung cancer (NSCLC) contributes about 85% of total lung cancer cases. An extensive number of risk factors are attributed to the progression of lung cancer. Epidermal growth factor receptor (EGFR), one of the most frequently mutant driver genes, is closely involved in the development of lung cancer through regulation of the PI3K/AKT and MAPK pathways. As a representative of precision medicine, EGFR-tyrosine kinase inhibitors (TKIs) targeted therapy significantly relieves the development of activating mutant EGFR-driven NSCLC. However, treatment with TKIs facilitates the emergence of acquired resistance that continues to pose a significant hurdle with respect to EGFR targeted therapy. In this review, the development of current approved EGFR-TKIs as well as the related supporting clinical trials are summarized and discussed. Mechanisms of action and resistance were addressed respectively, which serve as important guides to understanding acquired resistance. We also explored the corresponding combination treatment options according to different resistance mechanisms. Future challenges include more comprehensive characterization of unclear resistance mechanisms in different populations and the development of more efficient and precision synthetic therapeutic strategies.
根据世界卫生组织的最新报告，肺癌在全球范围内导致的死亡率高于其他癌症。非小细胞肺癌（NSCLC）约占肺癌病例总数的85%。肺癌的进展归因于大量的风险因素。表皮生长因子受体（EGFR）是最常发生突变的驱动基因之一，通过调节PI3K/AKT和MAPK信号通路密切参与肺癌的发生发展。作为精准医学的代表，EGFR酪氨酸激酶抑制剂（TKIs）靶向治疗显著缓解了激活突变型EGFR驱动的NSCLC的进展。然而，TKIs治疗会促使获得性耐药的出现，这仍然是EGFR靶向治疗面临的重大障碍。在这篇综述中，总结并讨论了当前已获批的EGFR-TKIs的发展以及相关的支持性临床试验。分别阐述了作用机制和耐药机制，这对理解获得性耐药具有重要指导意义。我们还根据不同的耐药机制探索了相应的联合治疗方案。未来的挑战包括更全面地表征不同人群中不明耐药机制，以及开发更有效、精准的综合治疗策略。
