Responses to the MET inhibitor tepotinib in gastric cancers with MET amplification or both high PD-L1 expression and an MET exon 14 skipping mutation.
JOURNAL OF CLINICAL ONCOLOGY(2022)
摘要
e16037 Background: Aberrant expression of MET involving MET exon 14 (METex14) alteration and high CNV, which leads to enhanced tumorigenesis. In addition, the PD-L1 (CD274) is often upregulated in cancers. This study characterized expressions of MET (including METex14 skipping mutation), PD-L1 and CD44 in human gastric cancer (GC) cell lines, and further characterized the differential susceptibility of these cell lines to tepotinib. Methods: We assessed the antitumor activity of tepotinib in GC cell lines. CNV analysis using targeted next-generation sequencing (NGS) techniques. The effect of tepotinib on cell viability (IC 50 ), apoptotic cell death, migration, the PD-L1, CD44 and c-MET signaling were evaluated by MTS assay, flow cytometry, wound-healing assay, western blotting, and qRT-PCR. Results: Tepotinib treatment showed dose-dependent growth inhibition of c-MET-amplified SNU620, MKN45, Hs746T, SNU638 and KATO III cells with concomitant induction of apoptosis. Tepotinib treatment also significantly reduced expressions of phospho-c-MET, total c-MET, VEGFR2, Snail and c-Myc protein in SNU620, MKN45 and Hs746T cells. Especially, tepotinib significantly reduced the expressions of CD44 and PD-L1 in METex14 skipping mutated Hs746T cells. In contrast, this drug was only slightly active against KATO III and SNU638 cells. Migrations were more reduced in the tepotinib-treated group than in the control group. Conclusions: These data show the possibility that tepotinib may have therapeutic effects in c-MET-amplified GC and both high PD-L1 expression and an MET exon 14 skipping mutation, suggesting that clinical studies need to confirm the therapeutic effect.
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关键词
met inhibitor tepotinib,gastric cancers,met exon
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