Abstract 1054: Targeting EGFR signaling by synthetic lethality for chemoprevention of lung cancer.
Authors: Hara Yannis , Huang Shaoyi , Wu Xiangwei 
Published: August 2014

Abstract
Background:
Despite continuing improvement in treatment strategy, lung cancer remains the leading cause of cancer death in the US with a low 5-year survival rate. The epidermal growth factor receptor (EGFR) plays an important role in carcinogenesis and tumour progression through activation mechanisms including overexpression, mutation, and autocrine ligand production. In the United States, activating EGFR mutations including L858R are estimated to occur in 15% of patients with primary lung adenocarcinomas. We recently proposed a new cancer chemoprevention approach SITEP (short-term intermittent therapy to eliminate premalignancy) to target the “drivers” of tumorigenesis to overcome the challenges in cancer chemoprevention. In a scientific proof-of-concept study, we demonstrated that a two-drug combination of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and a small molecule mimic of the mitochondrial protein Smac /DIABLO (Smac), through a synthetic lethal interaction, specifically targets the activation of KRAS signaling for lung cancer chemoprevention (Huang et al., CaPR 2011). Since activation of EGFR leads to the activation of KRAS signaling, we hypothesize that TRAIL and Smac mimic will specifically target mutant EGFR for apoptosis through synthetic lethality and can be used for lung cancer chemoprevention. Thus the aim of this study was to elucidate the mechanism and evaluate the efficacy of TRAIL and Smac mimic on the induction of apoptosis in EGFR (L585R) mutant lung cancer cells in vitro.
Methods:
To explore the mechanism of EGFR-L858R-mediated sensitization to TRAIL and Smac in vitro, a EGFR-L858R expressing plasmid was transfected into normal immortalized lung epithelial cells. Activation of downstream signaling molecules MAPK and the AKT was assessed. Modulation of TRAIL receptor expression was analyzed. The effect on TRAIL and Smac-mediated apoptosis was measured.
Results:
As expected, the overexpression of EGFR-L858 receptor leads to an activation of ERK and AKT by phosphorylation, an activation of c-Myc and a repression of c-FLIP. More importantly, expression of EGFR-L858R sensitized normal epithelial cells to TRAIL and Smac mimic-induced apoptosis. Various inhibitors targeting the MAPK and PI3K-AKT pathways are used to confirm this effects and the contribution of these pathways on apoptosis.
Conclusion:
Our results showed that TRAIL and Smac mimic selectively induced apoptosis in EGFR-L858R expressing lung epithelial cells in vitro. Further studies are required to elucidate detailed mechanism, and to test the efficiency of this selective therapeutic approach in the chemoprevention of lung cancer in animal models.
Citation Format: Yannis Hara, Shaoyi Huang, Xiangwei Wu. Targeting EGFR signaling by synthetic lethality for chemoprevention of 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 1054. doi:10.1158/1538-7445.AM2013-1054