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.