Data from Mutant LKB1 Confers Enhanced Radiosensitization in Combination with Trametinib in KRAS-Mutant Non–Small Cell Lung Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> The MEK inhibitor trametinib radiosensitizes KRAS-mutant non–small cell lung cancer (NSCLC) and is being tested clinically with chemoradiation. However, variability in response to trametinib suggests that additional pathways are involved. The mechanism of resistance to trametinib radiosensitization is still unknown.</p><p><b>Experimental Design:</b> We used a panel of <i>KRAS</i>-mutant NSCLC cells and tested the radiosensitization effects of trametinib by clonogenic survival assay. Then, we investigated the mechanisms underlying the resistance to the combination therapy through several knockout and overexpression systems. Finally, we validated our findings in syngeneic mouse models in a treatment setting that mimicked the standard of care in the clinic.</p><p><b>Results:</b> Radiosensitization by trametinib was effective only in <i>KRAS-LKB1</i>–mutated cells with wild-type (WT) p53, and we found that restoring <i>LKB1</i> expression in those cells blocked that sensitization. Trametinib and radiotherapy both induced senescence in a p53-dependent manner, but in WT <i>LKB1</i> cells, the combination also activated the AMPK-autophagy pathway to rescue damaged cells from senescence. <i>LKB1</i>-knockout or autophagy inhibition in WT <i>LKB1</i> cells potentiated trametinib radiosensitization. In syngeneic animal models of <i>Kras</i>-mutant lung tumors, <i>Lkb1</i>-knockout tumors were resistant to trametinib and chemoradiation given separately, but the combination greatly controlled tumor growth and prolonged survival.</p><p><b>Conclusions:</b> The <i>LKB1</i> mutation in <i>KRAS</i>-mutant NSCLC conferred enhanced radiosensitization in combination with trametinib. The WT LKB1 could activate autophagy through AMPK pathway to induce resistance to the combination of trametinib and radiation. The KRAS-LKB1 mutation could potentially be a biomarker to select patients for trametinib and radiotherapy combination therapy. <i>Clin Cancer Res; 24(22); 5744–56. ©2018 AACR</i>.</p></div>