SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations.

Summary 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 lung cancer patients with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. A 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 xenografts models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with a SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.