Activated forms of tyrosine kinases such as VEGFR, FGFR and PDGFR are known to play role in tumor angiogenesis, a process essential for growth of tumors. These receptors are activated selleck products by their correspond ing growth factors secreted by tumor cells resulting in proliferation, migration and survival of tumor endothe lial cells. Although VEGF RTKs are the major tar gets for dovitinib, preclinical studies have also shown that FGF signaling is a possible mechanism of escape from and resistance to anti VEGF therapy. There fore, dovitinibs uniqueness in inhibiting growth factor receptors including FGFR and VEGFR makes it stand out among other RTKs inhibitors. A high percentage of colorectal carcinomas over express a lot of growth fac tors and their receptors, including fibroblast growth fac tor and FGF receptor.

Takayama et al. have shown that over expression of FGFR corre lates with liver metastasis in CRC. Our results showed a decrease in phosphorylation of VEGFR and FGFR in two colon cancer cell lines tested. In vitro data in HCT116, HT 29 and SW 480 cell lines showed de creases in expression of all proteins in MAP kinase path way such as kRAS, bRAF and pERK. Previous studies have shown that use of MEK inhibitors impaired prolif eration thereby impacting a diverse array of cellular events, including differentiation, apoptosis, and angio genesis. However, Turke et al. have shown that MEK inhibitor led to activation of a parallel PI3K/AKT signaling pathway involving several feedback systems.

The vice versa has also been shown true in which inhibition of PI3K pathway activated MAP kinase path way, thereby decreasing the effectiveness of single agent targeted therapies. This suggests that concomitant inhibition of both pathways is necessary to block prolif eration and induce cell death and shrink the tumor. Since inhibition by dovitinib in these cell lines was an upstream of kRAS, a parallel inhibition of both RAS RAF MAPK and PI3K AKT suggest a synergistic effect of both pathways on downstream effectors of growth and proliferation. Our data also showed an inhibition of Brefeldin_A expression of pAKT in all three cell lines. Our results are in agreement with a recent report showing a con comitant down regulation of PI3K and MEK induced re gression of kRAS mutant cancers in vivo. Our results with wound healing assay showed a signifi cant decrease in wound repair with the use of combin ation of two as compared to either of the drugs alone confirmed a simultaneous inhibition of both signaling pathways which are known to contribute neverless to the inhibition of protein synthesis, cell growth, proliferation and survival. Lee et al. have shown that inhibition of FGFR and PDGFR starts as early as 4 h in the presence of Dovitinib.