Molecular mechanisms of sunitinib resistance in renal cell carcinoma

Renal cell carcinoma (RCC) is a treatment resistant cancer. The identification of the link between the von Hippel Lindau (VHL) gene and the vascular endothelial growth factor (VEGF) pathway has led to development of the multi-tyrosine kinase inhibitor sunitinib. The introduction of sunitinib in clinical practice for the treatment of metastatic RCC has significantly increased the overall survival of patients. However resistance to sunitinib is emerging as a challenge. About 30% of patients are intrinsically resistant to sunitinib and almost all patients who show initial response to sunitinib develop extrinsic (acquired) resistance after a median of 6-15 months. While the molecular mechanisms of sunitinib resistance are multifactorial, the emerging consensus is that, sustained VEGF/VEGF receptor (VEGFR) inhibition by sunitinib 'resets' the tumor microenvironment leading to the development of VEGF/VEGFRindependent alternate angiogenic pathways. This chapter summarises the advances in understanding of the molecular mechanisms of sunitinib resistance in RCC.