Abstract B41: Restoring sensitivity to anti-EGFR-based therapy in lung adenocarcinoma by downstream modulation of the FOXO1/KLF6 transcriptional network

Abstract

Abstract Anti-EGFR-based strategies have shown clinical efficacy in the treatment of metastatic lung adenocarcinoma. Nevertheless, treatment resistance invariably develops through either de novo activation of downstream RAS/AKT signaling or acquired mutations in the Epidermal growth factor receptor (EGFR). A more thorough molecular characterization of the downstream mediators of EGFR signaling may lead to the development of newer classes of targeted molecular therapies to treat resistant disease. Here we identify a transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that regulate response to anti-EGFR-based therapies in both cell culture and in vivo models of the disease. Specifically, inhibition of AKT signaling promotes FOXO1 stabilization resulting in transactivation of the KLF6 tumor suppressor gene and induction of apoptosis in lung adenocarcinoma cell lines. Furthermore, the use of FDA-approved drug trifluoperazine hydrochloride, a FOXO1 nuclear export inhibitor restores sensitivity to erlotinib-resistant cell lines through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft lung adenocarcinoma models. In addition, quantitative real-time PCR-based analysis and Western blotting confirm a significant correlation between activated oncognic EGFR signaling and downregulation of the FOXO1 and KLF6 tumor suppressor gene network in both primary human lung adenocarcinoma patient samples and a transgenic mouse model of the disease. Combined, these studies define a novel transcriptional network regulating oncogenic EGFR signaling and identify targeted molecular agents to restore chemosensitivity to anti-EGFR-based therapy in culture and in vivo. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B41.