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

• Published in: Cancer treatment reviews 2023-12, Vol.121, p.102645-102645, Article 102645
• Main Authors: Golijanin, Borivoj, Malshy, Kamil, Khaleel, Sari, Lagos, Galina, Amin, Ali, Cheng, Liang, Golijanin, Dragan, Mega, Anthony
• Format: Article
• Language: English
• Subjects: Clear cell; HIF; Metastasis; Renal cell carcinoma; Targeted therapy; VHL
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2023.102645

•Review on HIF and VHL in the pathogenesis of ccRCC.•HIF2a is a target of interest treatment of clear cell renal cell carcinoma.•Improved safety profile of drugs with targeting upstream of HIF2a.•Identification of novel resistance mechanisms can improve outcomes.•Numerous clinical trials are exploring this pathway. 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-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α 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 HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.