Abstract
Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations to the LKB1 tumor suppressor are common in NSCLC and are concurrent with activating mutations to the KRas oncogene. Genetic and mechanistic analyses of KRas/LKB1-null NSCLC tumors suggest these tumors are a phenotypically distinct subpopulation of NSCLC and the unique features of KRas/LKB1-null tumors have potential for therapeutic gain. In the exploration of the mechanism(s) behind increased cytotoxicity of KRas/LKB1-null NSCLC cells to 2-D-Deoxyglucose (2DG), we find that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological aggravation of ER stress. In a panel of NSCLC cell lines, LKB1 expression status correlated to differential expression of the ER stress markers, BiP and CHOP, with 2DG treatment. Treatment of isogenic LKB1-null NSCLC cells ectopically expressing LKB1 or a nonfunctional LKB1 with the ER stress activators, tunicamycin (Tm) or brefeldin A (BFA), revealed that expression of LKB1 increased cell viability and phosphorylation of AMPK. Conversely, isogenic LKB1-null NSCLC cells expressing nonfunctional LKB1 displayed increases in phosphorylation of the ER stress marker, eif2α and markers of ER stress mediated cell death (reactive oxygen species and cleaved caspase-9) following aggravation of ER stress with 2DG, Tm or BFA. The use of 2DG was effective in controlling the growth of KRas/LKB1-null tumors compared to KRas/LKB1-expressing tumors in transgenic NSCLC models and 2DG-treated KRas/LKB1-null NSCLC tumors displayed features consistent with 2DG treatment of in vitro KRas/LKB1-null NSCLC cell lines. Based upon these findings, we suggest that KRas/LKB1-null NSCLC tumors are more sensitive to pharmacological aggravation of ER stress and this approach has potential as a treatment for NSCLC patients whose tumors are defined as KRas/LKB1-null.
Citation Format: Landon J. Inge, Jacqueline M. Friel, Aaron Fowler, Amanda Richer, Timothy Whitsett, Nhan L. Tran, Ross M. Bremner. LKB1 loss sensitizes non-small cell lung cancer cells to aggravation of ER stress. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2014-5470