Increased Expression of AXL and c-MET in High-Grade Clear Cell Renal Cell Carcinoma and Its Association With VEGFR-TKI Treatment and PD-L1 Expression.

Cabozantinib, a newly developed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI), is an effective treatment for advanced renal cell carcinoma (RCC). However, the molecular mechanisms responsible for the superior effectiveness of cabozantinib to other drugs remain unclear. Since cabozantinib inhibits AXL and c-MET in addition to VEGFR, the expression of these molecules was immunohistologically examined in 110 cases of primary clear cell RCC (ccRCC) and eight of sunitinib (VEGFR-TKI)-treated primary ccRCC. AXL expression correlated with the primary tumor stage, while c-MET expression correlated with distant metastasis, the histological grade, and overall survival. Furthermore, the number of programmed death-ligand 1 (PD-L1)-positive tumor-infiltrating immune cells was higher in ccRCC tissues with high c-MET expression than in those with low c-MET expression. The expression of AXL and c-MET was higher in sunitinib-treated ccRCC tissues than in untreated tissues. These results suggest that AXL and c-MET play important roles in the progression of ccRCC and resistance to sunitinib. Furthermore, c-MET may modify the immune microenvironment by inducing PD-L1 expression in immune cells within RCC tissues. These molecular pathways may be related to responses to cabozantinib.