Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells ( p-value = 0.02). The drug response was cell-line-specific.

Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib.

The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinib-resistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC).

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