Dovitinib (TKI-258), a multi-target angiokinase inhibitor, is effective regardless of KRAS or BRAF mutation status in colorectal cancer

Abstract

We aimed to determine whether KRAS and BRAF mutant colorectal cancer (CRC) cells exhibit distinct sensitivities to the multi-target angiokinase inhibitor, TKI-258 (dovitinib). We screened 10 CRC cell lines by using receptor tyrosine kinase (RTK) array to identify activated RTKs. MTT assays, anchorage-independent colony-formation assays, and immunoblotting assays were performed to evaluate the in vitro anti-tumor effects of TKI-258. In vivo efficacy study followed by pharmacodynamic evaluation was done. Fibroblast Growth Factor Receptor 1 (FGFR1) and FGFR3 were among the most highly activated RTKs in CRC cell lines. In in vitro assays, the BRAF mutant HT-29 cells were more resistant to the TKI-258 than the KRAS mutant LoVo cells. However, in xenograft assays, TKI-258 equally delayed the growth of tumors induced by both cell lines. TUNEL assays showed that the apoptotic index was unchanged following TKI-258 treatment, but staining for Ki-67 and CD31 was substantially reduced in both xenografts, implying an anti-angiogenic effect of the drug. TKI-258 treatment was effective in delaying CRC tumor growth in vivo regardless of the KRAS and BRAF mutation status. Our results identify FGFRs as potential targets in CRC treatment and suggest that combined targeting of multiple RTKs with TKI-258 might serve as a novel approach to improve outcome of patients with CRC.