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

ABSTRACT 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.