Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer

作者：Kang, Jin; Deng, Qiu-Mei; Feng, Weineng; Chen, Zi-Hao; Su, Jun-Wei; Chen, Hua-Jun; Wang, Wen-xian; Zhang, Shirong; Wang, Qian; Chen, Zexin; Zhong, Wen-Zhao^*; Xu, Chun-wei^*; Yang, Jin-Ji^*

来源：Lung Cancer, 2023, 178: 66-74.

DOI：10.1016/j.lungcan.2023.01.017

• MET fusions
• EPHB4-MET
• Tyrosine kinase inhibitors
• Non-small cell lung cancer

Objectives: De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored.Materials and Methods: We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using tar-geted next-generation sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived organoid (PDO) model.Results: We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EPHB4, THAP5, TNPO3, and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mu-tations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, AKT, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation.Conclusion: MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

• 单位
  浙江大学; 中国科学院; 南京大学; 广东省心血管病研究所; 南方医科大学; 佛山市第一人民医院; 广东省人民医院