Here, we examined the impact of MET signaling inhibition by the highly selective and potent anti-MET small-molecule inhibitor tepotinib (62) in MET-driven gastric and lung cancer cell lines and in vivo xenografts and report that tepotinib sensitizes cancer cells to IR by depleting the de novo purine synthesis pathway and dNTPs via E2F1 axis in vitro. The gene discussed is E2F1; the disease is lung cancer.