Abstract
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 trametinib suggests that additional pathways are involved. The mechanism of resistance to trametinib radiosensitization is still unknown.Experimental Design: We used a panel of KRAS-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.Results: Radiosensitization by trametinib was effective only in KRAS-LKB1-mutated cells with wild-type (WT) p53, and we found that restoring LKB1 expression in those cells blocked that sensitization. Trametinib and radiotherapy both induced senescence in a p53-dependent manner, but in WT LKB1 cells, the combination also activated the AMPK-autophagy pathway to rescue damaged cells from senescence. LKB1-knockout or autophagy inhibition in WT LKB1 cells potentiated trametinib radiosensitization. In syngeneic animal models of Kras-mutant lung tumors, Lkb1-knockout tumors were resistant to trametinib and chemoradiation given separately, but the combination greatly controlled tumor growth and prolonged survival.Conclusions: The LKB1 mutation in KRAS-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. Clin Cancer Res; 24(22); 5744-56. ©2018 AACR.
Highlights
Lung cancer is the leading cause of death from cancer in the United States [1] and is commonly managed with various combinations of surgery, chemotherapy, and radiotherapy
Radiosensitization by trametinib was effective only in KRAS-Liver Kinase B1 (LKB1)–mutated cells with wild-type (WT) p53, and we found that restoring LKB1 expression in those cells blocked that sensitization
We found trametinib only sensitized the KRAS-LKB1 subtype of non–small cell lung cancer to radiotherapy and that restoring LKB1 expression in those cells blocked that sensitization
Summary
Lung cancer is the leading cause of death from cancer in the United States [1] and is commonly managed with various combinations of surgery, chemotherapy, and radiotherapy. About 85% of lung cancers are non–small cell lung cancer (NSCLC), and KRAS is the most often mutated oncogene in NSCLC [2]. Once cells are under stress, the interaction between p53 and MDM2 will be disrupted, stabilizing the p53 protein to trigger downstream signals [5]. LKB1 directly regulates the AMPK-mTOR pathway to control cell growth and metabolism, rendering LKB1-mutant cells resistant to metabolic stress [8]. Mutations in LKB1 in patients with lung cancer are strongly associated with KRAS mutations and a history of smoking [9]. Several studies have illustrated the relationship between LKB1 mutation and response to therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy [10,11,12,13,14]
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