Abstract 2899: Restoring sensitivity to anti-EGFR-based therapy in lung adenocarcinoma by downstream modulation of the FOXO1/KLF6 transcriptional network

Lung cancer is currently the leading cause of cancer-related death. This high mortality rate has prompted numerous exhaustive efforts to identify novel therapeutic targets and treatment modalities for this deadly disease. The characterization of specific signaling cascades involved in the development and progression of lung cancer has been instrumental in developing novel therapeutic strategies. This paradigm is best exemplified by recent studies demonstrating that the epidermal growth factor receptor (EGFR) is a critical diagnostic and therapeutic target in metastatic lung adenocarcinoma. The clinical utility of anti-EGFR-based strategies is, however, ultimately limited by primary or acquired drug resistance, that can develop through several distinct molecular mechanisms. Thus, a more complete molecular characterization of downstream mediators of both cancer progression and treatment resistance will allow for the development of rationally designed combination based therapies to overcome the specific molecular lesions driving the reistant phenotype. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. Here we identify a transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that regulates 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 the FDA-approved drug Trifluoperazine Hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restores sensitivity to erlotinib-resistant cell lines through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft lung adenocarcinoma models. Further validation of the requirement for KLF6 activation in erlotinib response was demonstrated by loss-of-function experiments, in which targeted reduction of KLF6 using sequence specific siRNAs abrogated the utility of erlotinib on lung tumors in vivo. In addition, a significant correlation between activated oncogenic 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 was observed. Combined, these studies define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs to restore chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2899. doi:10.1158/1538-7445.AM2011-2899