Zalaquett Ziad, Catherine Rita Hachem Maria, Kassis Yara, Hachem Samir, Eid Roland, Raphael Kourie Hampig, Planchard David
Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon.
Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon.
Cancer Treat Rev. 2023 May;116:102557. doi: 10.1016/j.ctrv.2023.102557. Epub 2023 Apr 7.
Lung cancer is the leading cause of cancer-related mortality worldwide. Detectable driver mutations have now changed the course of lung cancer treatment with the emergence of targeted therapy as a novel strategy that widely improved lung cancer prognosis, especially in metastatic patients. Osimertinib (AZD9291) is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat stage IV EGFR-mutated non-small-cell lung cancer. It was initially designed to target both EGFR-activating mutations and the EGFR T790M mutation as well, which is the most common resistance mechanism to first- and second-generation EGFR-TKIs. Following the FLAURA trial, osimertinib is now widely used in the first-line setting. However, resistance to osimertinib inevitably develops, with numerous mechanisms leading to its resistance, classified into two main categories: EGFR-dependent and EGFR-independent mechanisms. While EGFR-dependent mechanisms consist mainly of the C797S EGFR mutation, EGFR-independent mechanisms include bypass pathways, oncogenic fusions, and phenotypic transformation, among others. This review summarizes the molecular resistance mechanisms to osimertinib, with the aim of identifying novel therapeutic approaches to overcome osimertinib resistance and improve patient outcome.
肺癌是全球癌症相关死亡的主要原因。随着靶向治疗作为一种广泛改善肺癌预后（尤其是转移性患者）的新策略的出现，可检测到的驱动基因突变现已改变了肺癌的治疗进程。奥希替尼（AZD9291）是一种不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），用于治疗IV期EGFR突变的非小细胞肺癌。它最初被设计用于靶向EGFR激活突变以及EGFR T790M突变，后者是对第一代和第二代EGFR-TKI最常见的耐药机制。在FLAURA试验之后，奥希替尼现在广泛用于一线治疗。然而，对奥希替尼的耐药性不可避免地会出现，导致其耐药的机制众多，主要分为两大类：EGFR依赖性和EGFR非依赖性机制。虽然EGFR依赖性机制主要由C797S EGFR突变组成，但EGFR非依赖性机制包括旁路途径、致癌融合和表型转化等。本综述总结了对奥希替尼的分子耐药机制，旨在确定克服奥希替尼耐药性并改善患者预后的新治疗方法。
