MET Inhibition Results in DNA Breaks and Synergistically Sensitizes Tumor Cells to DNA-Damaging Agents Potentially by Breaching a Damage-Induced Checkpoint Arrest

Abstract

While recent studies implicate that signaling through the receptor tyrosine kinase MET protects cancer cells from DNA damage, molecular events linking MET to the DNA damage response machinery are largely unknown. Here, we studied the impact of MET inhibition by the small molecule PHA665752 on cytotoxicity induced by DNA-damaging agents. We demonstrate that PHA665752 reduces clonogenic survival of tumor cells with MET overexpression when combined with ionizing radiation and synergistically cooperates with ionizing radiation or adriamycin to induce apoptosis. In search of mechanisms underlying the observed synergism, we show that PHA665752 alone considerably increases γH2AX levels, indicating the accumulation of double-strand DNA breaks. In addition, PHA665752 treatment results in sustained high levels of γH2AX and phosphorylated ATM postirradiation, strengthening the assumption that MET inhibition attenuates postdamage DNA repair. PHA665752, alone or in combination with irradiation, leads also to a massive increase of γH2AX tyrosine phosphorylation and its subsequent interaction with the proapoptotic kinase JNK1. Finally, MET inhibition reduces activation of ATR, CHK1, and CDC25B and abrogates an associated DNA damage-induced S phase arrest. This indicates that MET inhibition compromises a critical damagedependent checkpoint that may enable DNA-damaged cells to exit cell cycle arrest before repair is completed.

c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo

“…Therefore, targeting c-MET may exhibit a synergistic effect with chemotherapy or radiotherapy (24,25). The present findings are consistent with previous studies (26)(27)(28)(29). It has been previously reported that the combination therapy of the anti-HGF monoclonal antibody AMG102 with the cytotoxic agent temozolomide or docetaxel enhances the anti-tumor action of temozolomide and docetaxel against glioblastoma multiforme (30).…”

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage–Induced Senescence Program in Gastric Cancer

“…45) may play a role (12,14,15). Interestingly, we observed different expression profiles of p21 and p16 in our panel of cell lines following the combined treatment.…”

“…As activation of the MET receptor was reported to protect cancer cells from IR-induced cell death by enhancing DNA damage repair activity (14,17), here we examined the effect of MET inhibition by the small-molecule tyrosine kinase inhibitor tepotinib (MSC2156119; Merck) alone or along with IR in MET-overexpressing human gastric cancer cell lines GTL-16, MKN-45, SNU-638, SNU-5, and KATO-II. Importantly, we observed that exposure of cells to low doses of tepotinib alone or in combination with IR resulted in a significant decrease in cell proliferation as indicated by the loss of incorporation of BrdUrd ( Fig.…”

“…A growing body of evidence suggests MET as a potential target for tumor sensitization to DNA-damaging agents (DDA), such as ionizing radiation (IR), which are commonly used in cancer therapy (14)(15)(16). In 2011, Medov a and colleagues (17) reported that inhibition of the MET receptor tyrosine kinase (RTK) impairs the ability of irradiated MET-overexpressing gastric cancer cell lines to properly execute DNA double strand breaks (DSB) repair.…”

The Novel ATP-Competitive Inhibitor of the MET Hepatocyte Growth Factor Receptor EMD1214063 Displays Inhibitory Activity against Selected MET-Mutated Variants

“…Bardelli and colleagues were the first to suggest that mutations in MET signaling lead to a substrate shift, that results in the activation of downstream effectors that are not activated by the wild-type receptor (9). This is further supported by the observation that MET mutants can couple with different signaling pathways, leading to diverse biologic consequences (10,(37)(38)(39)(40). These observations also support the findings by Graveel and colleagues who showed that knock-in mice expressing MET-mutated variants developed tumors of different histotypes (41).…”