Vascular endothelial growth factor (VEGF)-targeted agents have brought significant progress in pharmacotherapy of advanced renal cell carcinoma (RCC). Some RCCs, however, appear to have innate resistance to treatment. Moreover, majority of patients who primarily respond to VEGF-targeted therapy eventually develop disease progression after prolonged treatment. The mechanism of resistance is supposed to be so multifactorial that it cannot be explained by single molecular events. Despite various factors including cytokines, bone marrowderived cells, microenvironment, and genetic or epigenetic abnormality could be involved, tumor hypoxia seems to play one of crucial roles in most of the processes. The multiple mechanism in developing drug resistance might just represent the diversity of cellular response to hypoxia and nutrient deprivation, induced by the disruption of the blood vessels. In this chapter we comprehensively review current efforts aiming to clarify these process and to develop pharmacological strategies leading to overcome the drug resistance in RCC.
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