Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non–small cell lung cancer

Yifan Wang, Nan Li, Wen Jiang, Weiye Deng, Rui Ye, Cai Xu, Yawei Qiao, Amrish Sharma, Ming Zhang, Mien Chie Hung, Steven H. Lin

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5744-5756
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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