There have been recent improvements in the treatment for metastatic
renal cell carcinoma (RCC) with
receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of
Src kinase and the RTK may have synergistic effects to further improve
therapies on metastatic RCC. The effects of
Src kinase inhibitor
saracatinib and multiple RTK inhibitor
sunitinib on RCC cell line (ACHN) and Caki-1 were studied.
Saracatinib alone or in combination with
sunitinib inhibited the migration of ACHN and Caki-1 cells in vitro. Activation of migration related components FAK, P130Cas and
Paxillin were blocked by
saracatinib at 0.05- to 3-μM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to
sunitinib alone in the metastatic Caki-1 line. Molecular studies in Caki-1 showed that
saracatinib alone and in combination with
sunitinib inhibited phosphorylation of the cell progression regulator c-Myc in a dose-dependent manner.
Sunitinib alone or in combination suppressed cyclin-D1 expression with the combination showing greater dose-dependent effect.
Sunitinib inhibited
vascular endothelial growth factor (
VEGF) secretion through the inhibition of STAT3 signaling and
VEGF biosynthesis. HIF1-α expression in normoxic and hypoxic conditions in Caki-1 cells was inhibited by either
saracatinib or
sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting
Src kinase and RTK simultaneously with
saracatinib and
sunitinib resulted in 70-80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki-1 cells. The results show promise for combination targeted
therapy of RCC.