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

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