METTL3 inhibitor STM2457 impairs tumor progression and enhances sensitivity to anlotinib in OSCC.

OBJECTIVES: To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m(6)A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. MATERIALS AND METHODS: The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would-healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT-PCR, MeRIP-qPCR, immunofluorescence, and immunohistochemistry. RESULTS: STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis in vitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial-mesenchymal transition) features of OSCC cells. Remarkably, in vivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells. CONCLUSIONS: The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti-tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC.