Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44

Simple Summary High MET copy-number variation (CNV) and high MET protein expression via MET exon 14 skipping mutation (METex14SM) are associated with tumorigenesis; however, METex14SM is rare in GC, so target therapy is rarely applicable. In this study, we analyzed GC panels using targeted next-generation sequencing in GC cell lines and found that tepotinib demonstrated therapeutic effects in MET-amplified GC and those with high expressions of PD-L1, CD44, and METex14SM. Our in vitro findings indicate that tepotinib prevents GC-associated MET amplification and MET mutation. Both MET exon 14 skipping mutation (METex14SM) and high copy-number variation (CNV) lead to enhanced carcinogenesis; additionally, programmed-death ligand 1 (PD-L1) is often upregulated in cancers. In this study, we characterized the expression of MET (including METex14SM), PD-L1, and CD44 in human gastric cancer (GC) cells as well as the differential susceptibility of these cells to tepotinib. Tepotinib treatments inhibited the growth of five GC cells in a dose-dependent manner with a concomitant induction of cell death. Tepotinib treatments also significantly reduced the expression of phospho-MET, total MET, c-Myc, VEGFR2, and Snail protein in SNU620, MKN45, and Hs746T cells. Notably, tepotinib significantly reduced the expression of CD44 and PD-L1 in METex14SM Hs746T cells. By contrast, tepotinib was only slightly active against SNU638 and KATO III cells. Migration was reduced to a greater extent in the tepotinib-treated group than in the control group. Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.