肺癌是全球癌症相关死亡率的主要原因。现在，可检测的驱动基因突变已改变了肺癌治疗的进程，出现了以靶向治疗为新策略，广泛地改善了转移性患者的肺癌预后。奥西替尼（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），用于治疗四期EGFR突变的非小细胞肺癌。它最初的设计是同时针对EGFR激活突变和EGFR T790M突变，这是第一代和第二代EGFR-TKI最常见的耐药机制。在FLAURA试验后，奥西替尼现在广泛用于一线治疗。然而，抗奥西替尼的耐药性不可避免地出现，其抗药机制有许多，分为两个主要类别：EGFR依赖和EGFR非依赖机制。虽然EGFR依赖机制主要包括C797S EGFR突变，EGFR非依赖机制则包括绕过途径、致癌融合和表型转化等。本研究综述了奥西替尼的分子抗药机制，旨在寻找克服奥西替尼抗药性并改善患者预后的新疗法。版权所有© 2023 Elsevier Ltd.。保留所有权利。

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.Copyright © 2023 Elsevier Ltd. All rights reserved.