TY - JOUR
T1 - Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non–small cell lung cancer
AU - Wang, Yifan
AU - Li, Nan
AU - Jiang, Wen
AU - Deng, Weiye
AU - Ye, Rui
AU - Xu, Cai
AU - Qiao, Yawei
AU - Sharma, Amrish
AU - Zhang, Ming
AU - Hung, Mien Chie
AU - Lin, Steven H.
N1 - Funding Information:
This work was supported in part by the Mabuchi Program in Targeted Radiotherapy, Uniting Against Lung Cancer, NIH/NCI Lung Cancer SPORE (5P50CA070907), and Cancer Center Support (Core) Grant CA016672 from the NIH/NCI, to The University of Texas MD Anderson Cancer Center. Y. Wang is supported by a T.C. Hsu Memorial Scholarship from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. The authors thank Christine Wogan of the Division of Radiation Oncology at MD Anderson for editorial assistance. The authors thank Jie Zhang of the Center for Radiation Oncology Research at MD Anderson for technical assistance in histology.
Funding Information:
S.H. Lin is a consultant/advisory board member for AstraZeneca, Inc., and reports receiving commercial research grants from BeyondSpring Pharmaceuticals, Inc., Genentech, Hitachi Chemical Diagnostic. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported in part by the Mabuchi Program in Targeted Radiotherapy, Uniting Against Lung Cancer, NIH/NCI Lung Cancer SPORE (5P50CA070907), and Cancer Center Support (Core) Grant CA016672 from the NIH/NCI, to The University of Texas MD Anderson Cancer Center. Y. Wang is supported by a T.C. Hsu Memorial Scholarship from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. The authors thank Christine Wogan of the Division of Radiation Oncology at MD Anderson for editorial assistance. The authors thank Jie Zhang
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056592239&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056592239&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-1489
DO - 10.1158/1078-0432.CCR-18-1489
M3 - Article
C2 - 30068711
AN - SCOPUS:85056592239
SN - 1078-0432
VL - 24
SP - 5744
EP - 5756
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -