Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
Future Oncol. 2019 Feb;15(6):637-652. doi: 10.2217/fon-2018-0736. Epub 2018 Nov 8.
While the development of EGFR-targeted tyrosine kinase inhibitors (TKIs) has revolutionized treatment of EGFR mutation-positive non-small-cell lung cancer, acquired resistance to therapy is inevitable, reflecting tumor evolution. Recent studies show that EGFR mutation-positive non-small-cell lung cancer is highly heterogeneous at the cellular level, facilitating clonal expansion of resistant tumors via multiple molecular mechanisms. Here, we review the mechanistic differences between first-, second- and third-generation EGFR-targeted TKIs and speculate how these features could explain differences in clinical activity between these agents from a clonal evolution perspective. We hypothesize that the molecular dissection of tumor resistance mechanisms will facilitate optimal sequential use of EGFR TKIs in individual patients, thus maximizing the duration of chemotherapy-free treatment and survival benefit.
虽然表皮生长因子受体（EGFR）靶向酪氨酸激酶抑制剂（TKI）的发展彻底改变了 EGFR 突变阳性非小细胞肺癌的治疗方法，但治疗耐药性是不可避免的，这反映了肿瘤的进化。最近的研究表明，EGFR 突变阳性非小细胞肺癌在细胞水平上具有高度异质性，通过多种分子机制促进耐药肿瘤的克隆扩增。在这里，我们回顾了第一代、第二代和第三代 EGFR 靶向 TKI 的机制差异，并从克隆进化的角度推测这些特征如何解释这些药物在临床活性方面的差异。我们假设对肿瘤耐药机制的分子剖析将有助于在个体患者中优化 EGFR TKI 的序贯使用，从而最大限度地延长无化疗治疗的持续时间和生存获益。
