Alternative pathways to the
VEGF, such as
hepatocyte growth factor or HGF/c-met, are emerging as key players in
tumor angiogenesis and resistance to anti-
VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting the
VEGF and c-met pathways in
clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O
tumor pieces and treated with either a selective
VEGF receptor tyrosine kinase inhibitor,
axitinib (36 mg/kg, 2×/day); a c-met inhibitor,
crizotinib (25 mg/kg, 1×/day); or combination. We further tested this
drug combination in a human ccRCC patient-derived xenograft, RP-R-01, in both
VEGF-targeted
therapy-sensitive and -resistant models. To evaluate the resistant phenotype, we established an RP-R-01
sunitinib-resistant model by continuous
sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01-bearing mice. Treatment with single-agent
crizotinib reduced
tumor vascularization but failed to inhibit
tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the
sunitinib-resistant
tumors. In contrast,
axitinib treatment was effective in inhibiting angiogenesis and
tumor growth in both models, with its antitumor effect significantly increased by the combined treatment with
crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant
tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined
VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first- and second-line setting.