非小细胞肺癌（NSCLC）中的新生间充质向上皮转化（MET）基因融合是MET酪氨酸激酶抑制剂（TKI）的一个有前途的靶点。我们旨在研究新生MET融合阳性NSCLC患者靶向治疗与耐药机制的反应，因为这些尚未得到全面探讨。我们使用目标下一代测序检查了4,429名晚期NSCLC患者的MET融合，并使用RT-PCR验证了结果。我们分析了携带MET融合的细胞模型，并建立了患者衍生的器官样（PDO）模型。我们发现13名（0.29％，13/4429）患者携带新生MET融合，并发现EPHB4、THAP5、TNPO3和DST为新的MET融合伴侣。与MET融合共存的最常见的基因是TP53突变。在接受MET TKI治疗的12名患者中，2名患者实现了稳定疾病，6名患者实现了部分缓解，4名患者经历了进展性疾病。体外研究表明，EPHB4-MET是一个功能性驱动基因。MET抑制剂显著抑制了EPHB4-MET过表达细胞下游STAT3、AKT和ERK1/2的增殖和磷酸化。在获得MET TKI耐药后，携带MET融合的患者发现获得了MET D1228H/N或D1246N突变。Tivantinib在获得MET D1228N突变的PDO模型中显示出最佳的抑制效果。 MET融合发生在NSCLC患者的罕见亚群中，并代表了一个有前途的治疗靶点。MET次生突变D1228H / N或D1246N是MET抑制剂在新生MET融合患者中潜在的耐药机制。 版权所有©2023年作者。 Elsevier B.V.出版保留所有权利。

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.We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted 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.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 mutations. 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.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.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.