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

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; &lt;i&gt;KRAS&lt;/i&gt;-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 &lt;i&gt;KRAS&lt;/i&gt;-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring &lt;i&gt;KRAS&lt;/i&gt; mutations.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; 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 &lt;i&gt;KRAS-&lt;/i&gt;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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in &lt;i&gt;KRAS&lt;/i&gt;-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 &lt;i&gt;KRAS&lt;/i&gt;-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; 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 &lt;i&gt;KRAS&lt;/i&gt;-mutant lung cancers. &lt;i&gt;Clin Cancer Res; 23(22); 6993–7005. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;