Abstract 338: Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response

Abstract

Abstract Lung cancer is the leading cause of cancer-related mortality in the world killing more than one million people each year. Therapeutic resistance remains a significant clinical hurdle, contributing to a five-year survival rate of less than 5% in advanced lung cancer. The mechanisms of therapeutic resistance remain poorly understood and thus difficult to combat therapeutically. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and up-regulation of pro-survival Bcl-2 family members. Mcl-1 is over-expressed across many tumor types and correlates with poor patient prognosis and therapeutic resistance. We hypothesize that activation of the TWEAK-Fn14 signaling axis can induce therapeutic resistance through Mcl-1, and that Mcl-1 suppression can sensitize lung cancer cells to therapeutic insult. Here we demonstrate that both Fn14 and Mcl-1 are over-expressed and correlated in primary patient lung tumors. Mcl-1 expression correlates with both advanced stage lung cancer and poor patient prognosis. TWEAK stimulation of non-small cell lung cancer (NSCLC) cell lines induces Mcl-1 protein expression in a NF-κB-dependent manner. TWEAK exposure completely abrogates the cell killing effects of cisplatin or radiation treatment in NSCLC cell lines, and this TWEAK-induced protection is dependent on Mcl-1 expression. The suppression of Mcl-1 through RNAi or a novel Mcl-1 inhibitor (EU-5148) enhances the cell killing effects of cisplatin or radiation and completely blocks TWEAK-induced cell survival, whereas Bcl-2 and Bcl-xL inhibition have lesser effect on TWEAK-induced survival. The specificity of EU5148 is demonstrated through abrogation of the protein-protein interaction of Mcl-1 and Bim, with no effect on the interaction of Bcl-xL and Bim. Moreover, EU-5148 treatment inhibits cell survival across a panel of NSCLC cell lines, representing a range of histological subtypes and driver mutations, such as EGFR and KRAS. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival, and open new therapeutic avenues to abrogate the high mortality rate seen in advanced NSCLC. Citation Format: Timothy G. Whitsett, Ian T. Mathews, Michael H. Cardone, Ryan J. Lena, William E. Pierceall, Michael Bittner, Chao Sima, Janine LoBello, Glen J. Weiss, Nhan L. Tran. Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. [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 338. doi:10.1158/1538-7445.AM2014-338