Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives

• Sunitinib resistance in renal cell carcinoma appears to be transient and reversible.
• Tumor hypoxia plays a crucial role in several resistance mechanisms.
• Hypoxia-mediated cMET signaling leads to an increased malignant potential.
• Targeting cMET seems to be the most promising pharmacological treatment option.
• DNA promoter hypermethylation could represent promising predictive factors.

The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.