Patients with recurrent or metastatic renal cell carcinoma (mRCC) usually develop resistance to targeted tyrosine kinase inhibitors (TKI). Recently, FDA-approved cabozantinib is found to inhibit pathways linked to TKI resistance. Although cabozantinib is believed to be a new gold standard in managing TKI-resistant mRCC, it is still possible that mRCC can develop resistance to prolonged cabozantinib treatment by changing intracellular phosphorylation dynamics. In this study, 786-O was used for prolonged cabozantinib treatment for more than 4 months. Using quantitative phosphoproteomic approach, we tried to identified dysregulated pathways in prolonged cabozantinib treatment