Abstract 1616: The anti-tumor effect of TAE226, dual inhibitor of FAK and IGF-IR, on non-small-cell lung cancer with EGFR mutation

Abstract

Abstract Background: TAE226 is the small molecule inhibitor that has been originally considered to inhibit focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). FAK and IGF-IR have been reported to be up-regulated in non-small cell lung cancer (NSCLC), suggesting their important roles on pathogenesis of NSCLC. In this study, we examined the anti-tumor effect of TAE226 on NSCLC cells in vitro and in vivo. Methods: We used NSCLC cell lines consisting of 4 EGFR-mutant cell lines (PC9, H3255, HCC827, H1975) and 3 EGFR-wild type cell lines (H1819, H1299, A549). We also used PC9-derived gefitinib-resistant cell line (RPC9). Anti-proliferative effect of TAE226 was examined with MTS assay. The status of EGFR and its downstream molecules was analyzed by Western blotting. The binding affinity of TAE226 to EGFR protein in the presence of ATP was compared between mutant and wild type EGFR proteins. The effect of TAE226 on xenograft mouse models was examined. Results: The value of IC50 (µmol/L) for EGFR-mutant cells (PC-9, H3255, HCC827, H1975 [T790M], and RPC-9 [T790M]) ranged from 0.086 to 0.31 and that of EGFR wild type cells (H1819, H1299, and A549) ranged from 1.4 to 4.7, indicating that EGFR-mutant cells are sensitive to TAE226. Western blotting assay showed that TAE226 preferentially inhibited phospho-EGFR and phospho-AKT. The binding affinity of TAE226 to mutant EGFR protein was 1000 times higher compared with wild-type EGFR protein. TAE226 via oral administration with dose of 30 mg/kg and 60 mg/kg exhibited significant inhibition of tumor growth in EGFR-mutant tumors compared with EGFR-wild type tumors without major toxicity or weight loss. These results suggested that safety of TAE226 within the treatment dose for EGFR-mutant cells in vivo. Conclusions: We indicated that TAE226 showed anti-tumor effect on EGFR-mutant cells and overcame resistance to gefitinib. Our results suggest that TAE226 will be expected as a novel strategy for NSCLC with EGFR mutation regardless of the presence of secondary T790M mutation. 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 1616.