获得性耐药性仍然是致癌基因成瘾癌症的一个主要问题。阐明耐药机制可以为靶向治疗复发的患者提供合理的治疗策略，同时提供对肿瘤进化的见解。在这里，我们报告了在用 ROS1 抑制剂序贯治疗后，获得 MET 扩增作为 ROS1 重排肺腺癌的耐药驱动因素。随后劳拉替尼加卡马替尼（一种 MET 选择性抑制剂）的联合治疗诱导了颅内和颅外肿瘤反应。复发时，耐药肿瘤的测序显示存在 MET D1246N 突变和 MET 扩增缺失。我们对一系列肿瘤和血浆样本进行了综合分子分析，揭示了 ROS1 融合驱动器和 MET 旁路轴在基因组和蛋白质水平上的动态变化以及多克隆耐药性的出现。该案例说明了序贯靶向治疗的纵向肿瘤进化的复杂性，强调了当前精准肿瘤学范式中所面临的挑战以及开发防止耐药性的方法的重要性。© 2023。作者。

Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.© 2023. The Author(s).