Abstract 3634: Overcoming drug resistance to EGFR-tyrosine kinase inhibitors by FUS1 or FHIT-gene therapy in human lung cancer

Abstract

Abstract Dysregulation of the epidermal growth factor receptor (EGFR) and apoptotic pathways is a hallmark of human lung cancer and regulate tumor cell proliferation, survival, angiogenesis, and metastasis. Inhibition of oncogenic EGFR activity is proving to be an effective therapeutic strategy for lung cancer. Though EGFR-tyrosine kinase inhibitors (TKIs) are promising drugs, resistance occurs frequently. ZD6474 is an orally available small-molecule that inhibits both EGFR and VEGFR2 tyrosine kinases. FUS1 and FHIT are novel tumor suppressor genes identified in the human chromosome 3p21.3 and 3p14.2 regions, respectively and have been shown to suppress tumor cell growth by induction of apoptosis and down-regulation of multiple oncogenic tyrosine kinase activities in human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. We evaluated the therapeutic effects of EGFR-TKIs at dose levels equivalent to those of steady-state serum levels achieved in the clinic as single agents and in combination with FUS1- or FHIT-nanoparticle-mediated gene therapy in NSCLC cells. We found that expression of wild type FUS1 or FHIT sensitized NSCLC cells to ZD6474 treatment (at 2µM), as shown by significantly enhanced inhibition of tumor cell growth in a cell proliferation assay. A combination treatment with FUS1-nanoparticles and ZD6474 also significantly enhanced inhibition on tumor cell-induced colony formation in H322 cells compared to treatment with either agent alone. Combination treatment with ZD6474 and FUS1 or FHIT-nanoparticles increased down-regulation of the EGFR signaling pathway and up-regulation of the apoptosis pathway as indicated by the reduced expression of the phosphorylated Akt and ERK1/2 and by enhanced expression of cleaved PARP on Western blots. We found that the expression level of p-Met, which is one of acquired resistant factors to EGFR-TKIs, was reduced by FHIT-gene therapy in H1975 cells. We evaluated the antitumor effects of combination therapy using a fluorometric migration assay and found that the migration of H1299-GFP cells were inhibited by co-treated with ZD6474 and FHIT-gene therapy. Our findings imply that a combination treatment with FUS1 or FHIT-gene therapy and ZD6474 may be a useful strategy for enhancing lung cancer therapy. (supported by NIH Lung SPORE P50CA70907 and RO1CA116322) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3634.