Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.

Tepotinib是一种口服MET抑制剂，被批准用于具有MET外显子14（METex14）跳跃突变的转移性非小细胞肺癌（NSCLC）。通过MET扩增或METex14跳跃突变检查未经治疗的或对tepotinib耐药的细胞，可以确定其他受体酪氨酸激酶（RTK），它们在tepotinib暴露前共存于细胞中，并在对tepotinib产生耐药性时变得更加突出。在一小群患有使用tepotinib治疗的MET基因改变的肺癌患者中，在基线时发现了其他RTK的基因拷贝数增加，并影响了治疗结果。含有Src同源性2结构域的磷酸酶2（SHP2）抑制剂延迟了tepotinib耐药性的出现，并与tepotinib在未治疗和耐tepotinib的细胞以及异种移植模型中协同作用。