Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China.
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Respir Res. 2023 Jan 25;24(1):28. doi: 10.1186/s12931-023-02329-1.
BACKGROUND: The Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies. METHODS: Eighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing. RESULTS: MET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs. CONCLUSIONS: MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.
背景：间质上皮转化因子（MET）基因编码一种受体酪氨酸激酶，在癌症中具有多种功能。MET 外显子 14 跳跃改变和高水平 MET 扩增是非小细胞肺癌（NSCLC）患者的致癌和可靶向遗传改变。对酪氨酸激酶抑制剂（TKI）的耐药性一直是靶向治疗的主要挑战，这会损害其临床疗效。
方法：86 例 NSCLC 患者根据检测 MET 酪氨酸激酶结构域（TKD）突变的时间分为三组（队列 1：基线；队列 2：MET-TKI 治疗后；队列 3：EGFR-TKI 治疗后）。对基线和配对 TKI 治疗样本进行靶向下一代测序分析。
结果：MET-TKI 治疗后 METex14 阳性 NSCLC 患者 MET TKD 突变高度普遍，包括 L1195V、D1228N/H/Y/E、Y1230C/H/N/S 和密码子 D1228 和 M1229 内的双突变。MET TKD 的错义突变也在基线和 EGFR-TKI 治疗后样本中被发现，其分布模式与 MET-TKI 治疗后样本不同。值得注意的是，H1094Y 和 L1195F 在 MET-TKI 治疗患者中不存在，是 EGFR-TKI 治疗患者中 MET TKD 突变的主要类型。在治疗初治患者中未发现的 D1228H 也占 EGFR-TKI 治疗样本中所有 MET TKD 突变的 14.3%。两名一线 EGFR-TKI 治疗后获得 MET-V1092I 或 MET-H1094Y 的基线 EGFR 敏感突变患者，其临床症状总体改善，随后接受 MET-TKI 靶向治疗。
结论：在基线和接受 TKI 治疗的患者中均发现 MET TKD 突变。MET-H1094Y 可能在 NSCLC 中发挥致癌作用，并可能导致对 EGFR-TKI 的获得性耐药。初步数据表明，获得 MET-V1092I 或 MET-H1094Y 的 EGFR 突变型 NSCLC 患者可能受益于 EGFR-TKI 和 MET-TKI 的联合治疗，为个体化治疗提供了思路。
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