Synergy of WEE1 and mTOR Inhibition in Mutant <i>KRAS</i>-Driven Lung Cancers.

Abstract

<b>Purpose:</b><i>KRAS</i>-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multitargeted therapy may offer a plausible strategy to effectively treat <i>KRAS</i>-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring <i>KRAS</i> mutations.<b>Experimental Design:</b> We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human <i>KRAS-</i>mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment.<b>Results:</b> We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in <i>KRAS</i>-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in <i>KRAS</i>-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1.<b>Conclusions:</b> These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with <i>KRAS</i>-mutant lung cancers. <i>Clin Cancer Res; 23(22); 6993-7005. ©2017 AACR</i>.