Evolution of the HIF targeted therapy in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligasecomplex essential for degradation of the hypoxia-inducible factors (HIF) 1 alpha and 2 alpha. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2 alpha subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2 alpha-focused therapeutic approaches, and opportunities for ccRCC treatment.

Automated summary

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, and its pathogenesis is mainly caused by biallelic loss of the tumor suppressor gene VHL. Dysfunctional degradation of HIF due to VHL loss leads to overaccumulation of HIF, resulting in the activation of genes responsible for cell survival and proliferation in ccRCC. Previous therapies have targeted downstream effectors of HIF, but there is now a focus on interfering with upstream targets.