Abstract 106: A requirement for FADD and its phosphorylation for KRAS-driven oncogenesis

Abstract

Abstract Lung cancer accounts for 27% of all cancer deaths worldwide. 80% of these deaths are due to a specific subtype Non-small cell lung cancer (NSCLC). Almost half of all NSCLC patients carry gatekeeper mutations in the EGFR/KRAS pathway. Although KRAS mutations are the most prevalent mutations in human cancers, therapies targeting KRAS have fallen short. Tyrosine kinase inhibitors have been successful in NSCLC patients with mutant or amplified EGFR, however resistance to these inhibitors is common. Thus therapies targeting mutant KRAS or its downstream effectors are desperately needed for the treatment of NSCLC. FAS Associated Death Domain (FADD) is a well characterized adaptor protein involved in death receptor mediated apoptosis, but more recently has been implicated in the regulation of other cellular functions such as cell cycle and proliferation. Increasing evidence suggests that it is FADD's phosphorylated state which regulates these non-apoptotic signaling pathways. We and others have previously identified phosphorylated FADD as a predictor of aggressiveness and clinical stage in lung and head and neck cancer patients, respectively. Using non-invasive bioluminescence and µCT imaging in a Kras driven mouse model of NSCLC, we demonstrate the requirement for FADD in tumor progression. Lung-specific activation of KrasG12D and simultaneous FADD deletion resulted in reduced lung tumor burden. Furthermore lung lesions of KrasG12D FADD null mice were significantly smaller with a decrease in proliferative index. Similar findings were obtained in MEFs, where siRNA mediated Kras knockdown or the use of MEK inhibitors resulted in a Kras dependent decrease in FADD phosphorylation, decrease in cell cycle progression and cell proliferation. These data propound the phosphorylation of FADD as a downstream event of Kras signaling and demonstrate its requirement for Kras dependent neoplasia in a mouse model for NSCLC. In summary our findings demonstrate that elevated FADD and phosphorylated FADD levels are predictive of poor survival in an animal model of NSCLC agreeing with clinical findings. Furthermore, it implicates phosphorylation of FADD downstream of KRAS activation and thus suggests FADD phosphorylation as a valid target in the treatment of NSCLC patients. Citation Format: Brittany M. Bowman, Stefanie Galban, Benjamin A. Hoff, Kevin A. Heist, Jennifer L. Boes, Craig J. Galban, Rajiv M. Patel, Jianke Zhang, Brian D. Ross, Alnawaz Rehemtulla. A requirement for FADD and its phosphorylation for KRAS-driven oncogenesis. [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 106. doi:10.1158/1538-7445.AM2014-106