Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer

Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). In view of the strong association between MET and SRC identified by direct regulation, growth factor-induced MET activation was suppressed by pretreatment with the SRC inhibitor, dasatinib, and downstream phosphorylation of AKT and ERK partially decreased, which suggested that SRC activation was essential for ligand-dependent and -independent activation of MET. Considering that both the activation of MET and SRC was required in ligand-dependent and -independent MET activation, the antitumor effect of concurrent inhibition of MET and SRC was examined, and it was demonstrated that combination treatment exerted increased viability inhibition and apoptosis enhancement in mutant and wild type RAS colon cancer cells. Therefore, combinational inhibition of MET and SRC may be a promising strategy for the treatment of CRC.