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

SUBMITTER: Medova M 

PROVIDER: S-EPMC3092265 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature