传统上，D1228 E/G/H/N 突变被认为会导致 I 型 MET-TKI 耐药。我们报告了一名 75 岁女性，患有携带 MET 外显子 14 跳跃突变的非小细胞肺癌，她在卡马替尼治疗诱导下出现了获得性 MET D1228H 突变。有趣的是，该患者对二线沃利替尼治疗表现出明显的反应，反应持续时间为 19 个月，并且出现了几个额外的转移病灶。再次活检样本的病理评估显示为腺癌，靶向下一代测序显示 MET D1228H 突变缺失，并存在 MET p.Y1230N 突变。作为回应，治疗方案进行了修改，包括每天服用 60 毫克卡博替尼，这导致肿瘤尺寸适度缩小。耐药突变的转变表明不同的Ib MET抑制剂可能表现出不同的耐药机制。我们呼吁基于患者来源的临床前模型（包括患者来源的肿瘤样细胞簇、患者来源的类器官和患者来源的异种移植物）进一步研究耐药性。© 2024。作者。

Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts.© 2024. The Author(s).