Abstract 2281: LKB1 loss leads to activation of the CREB transcription factor and sensitivity to MEK inhibition in human lung cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Loss of the LKB1 tumor suppressor is one of the most common genetic events in lung adenocarcinoma, and improved understanding of the cellular phenotypes and molecular pathways activated in these tumors will aid the development of therapeutic strategies targeting LKB1-deficient cancers. Methods: We analyzed gene expression patterns of LKB1 loss among resected lung adenocarcinomas, non-small cell lung cancer (NSCLC) cell lines, and tumors from a murine model of LKB1-deficient, KRAS mutant lung cancer. From this analysis we derived a gene expression signature of LKB1 loss in resected lung adenocarcinomas and assessed its performance in predicting LKB1 loss in multiple clinical and cell line test sets. We identified four ‘nodes’ of transcriptional regulation and compared the resulting gene lists to various collections of gene sets to identify putative biological phenotypes responsible for their expression. Furthermore, our LKB1-deficient signature was then used in conjunction with two compendia of in vitro drug sensitivity data to identify inhibitors with greater efficacy in cell lines that lacked LKB1. We then observed changes in gene expression, pathway activation, and drug sensitivity in three cell lines after stably re-expressing LKB1. Results: Our LKB1-deficient gene expression signature is significantly associated with LKB1 mutations, with sensitivity of 85% and specificity of 82% in independent testing cohorts (p<1E-10). Furthermore, the group of tumors identified by our model has low prevalence of EGFR mutations and never smokers, which recapitulates well-characterized clinical and molecular features of LKB1-deficient tumors. However, the gene expression pattern we observe bears little resemblance to the dysregulated genes observed in murine models of LKB1 loss. Based on analysis of our validated signature, we identify up-regulation of oxidative phosphorylation and activation of NRF2-driven oxidative stress response pathway in tumors lacking LKB1. Furthermore, we find that increased activity of the CREB transcription factor is a defining feature of these tumors, and show that this pathway is associated with in vitro sensitivity to MEK inhibition. Restoring LKB1 in three NSCLC cell lines reverses these phenotypes, with down-regulation of the LKB1-deficient gene expression signature, attenuation of the activity of a CREB-driven luciferase reporter, and increased resistance to the MEK inhibitor selumetinib. Conclusions: We find that the biology of human LKB1-deficient lung adenocarcinomas differs substantially from what is observed in the murine model. Moreover, our analysis of dysregulated pathways in human disease gives insight into pathway activation and biological phenotypes of these tumors, and specifically identifies MEK as a therapeutic target to which LKB1-deficient tumors show increased susceptibility. Citation Format: Jacob M. Kaufman, Joseph Amann, Kyungho Park, David Carbone. LKB1 loss leads to activation of the CREB transcription factor and sensitivity to MEK inhibition in human lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2281. doi:10.1158/1538-7445.AM2013-2281