Department of Medical and Surgical Sciences for Children and Adults, Division of Oncology, University-Hospital of Modena and Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy.
Department of Medical and Surgical Sciences for Children and Adults, Division of Oncology, University-Hospital of Modena and Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy.
Crit Rev Oncol Hematol. 2018 Mar;123:149-161. doi: 10.1016/j.critrevonc.2018.01.013. Epub 2018 Feb 6.
In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months. Many genetic aberrations have been described as possible mechanisms of EGFR TKIs acquired resistance and can be clustered in four main sub-groups: 1. Development of secondary EGFR mutations; 2. Activation of parallel signaling pathways; 3. Histological transformation; 4. Activation of downstream signaling pathways. In this review we will describe the molecular alterations underlying each of these EGFR TKIs resistance mechanisms, focusing on the currently available and future therapeutic strategies to overcome these phenomena.
在过去的几年中，针对表达致癌驱动突变（例如 EGFR）的非小细胞肺癌（NSCLC）的靶向治疗的发展改变了这一特定少数患者的临床管理和生存结果。几项 III 期临床试验证明了表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs）在 EGFR 突变型 NSCLC 患者中的疗效优于化疗。然而，在绝大多数情况下，EGFR TKIs 在 8-12 个月内失去临床活性。已经描述了许多遗传异常作为 EGFR TKI 获得性耐药的可能机制，并可以分为四个主要亚组：1. 继发 EGFR 突变的发展；2. 平行信号通路的激活；3. 组织学转化；4. 下游信号通路的激活。在这篇综述中，我们将描述这些 EGFR TKI 耐药机制背后的分子改变，重点介绍目前可用的和未来克服这些现象的治疗策略。
