(809.5) cMET inhibition potentiates the tumor-selective damaging effects of NQO1-bioactivatable agents by compromising DNA repair

Poster Board Number: A313

Snehal Bhandare (IU School of Medicine), I-Ju Yeh (Indiana University School of Medicine), Jon-Luc Poirier (Indiana University School of Medicine), Edward Motea (Indiana University School of Medicine, Simon Comprehensive Cancer Center, Indiana University)

The overall prognosis for solid tumors overexpressing mesenchymal-epithelial transition factor (cMET) receptor tyrosine kinase and NADPH:Quinone oxidoreductase 1 (NQO1) is poor, and innovative treatment strategies that selectively target these cancers are critically needed. Recent studies have implicated cMET in the activation of PARP1, a critical factor involved in DNA damage response and repair. Therefore, targeting cMET is an attractive strategy for cancer therapy.  However, the overall efficacies of cMET inhibitors and NQO1 bioactivable agents are limited due to dose-limiting toxicities and lack of tumor selectivity at high concentrations as a monotherapy. Here, we report that  the combination treatment with sublethal doses of cMET inhibitors (some in clinical trials and FDA-approved) and β-lapachone (β-lap, an NQO1-bioactivatable drug in clinical trials) induced synergistic lethality in cancer cells in an NQO1-dependent manner. Mechanistically, a sublethal dose of β-lap creates reactive oxygen species (ROS) that damage DNA nucleobases (e.g., 8-oxoguanine) but rapidly gets repaired by the ability of ROS-activated cMET to enhance PARP1 activity for efficient DNA damage repair in NQO1+ cells.  Thus, β-lap in combination with cMET inhibition elevated DNA damage by compromising DNA repair, increased double-strand break (DSB) formation and promoted tumor selective apoptosis in NQO1+cancer cells. We further determined that the combination treatment significantly inhibit tumor growth in 3D spheroids. Our results add a new strategy for personalized therapy: the targeting of cMET in NQO1+ cancers to potentiate the toxic effects of sub-lethal doses of NQO1-bioativatable agents and cMET inhibitors.

Keywords: β-Lapachone, NQO1, ROS, cMET, PARP1, DNA repair

This work was supported by Indiana CTSI Showalter Trust and NIH/NCI R21 CA253645 to EAM. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.