Dr Basin on Pharmacological Inhibition of Hsp70 in Belzutifan-Resistant RCC

Michael Basin, MD, urology resident, SUNY Upstate Medical University, discusses how the pharmacological inhibition of the molecular chaperone Hsp70 overcomes belzutifan (Welireg) resistance in clear cell renal cell carcinoma (RCC).

Systemic therapies, including combination therapy with VEGF TKIs and checkpoint inhibitors and dual checkpoint blockade have redefined the treatment landscape in RCC. Additionally, in August 2021, the FDA approved belzutifan for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery. Although these approaches have shown improved outcomes in the advanced setting, not all patients will respond to these agents due to acquired or inherent resistance, Basin says.

As such, investigators sought to determine the relationship between Hsp70 and belzutifan resistance. Hsp70 is a molecular chaperone that helps stabilize client proteins, protecting them from degradation. Through its interaction with hypoxia-inducible factor (HIF)–2α, Hsp70 may help maintain HIF2α stability in clear cell RCC. To investigate this further, cell line models of VHL-null clear cell RCC were treated with belzutifan. Immunoblotting was used to measure HIF2a expression and degradation levels. Findings from the analysis showed that inhibition of Hsp70 led to reduced levels of HIF2α, preventing tumor cell proliferation, Basin explains. These data show proof-of-principle that Hsp70 could represent another potential target in cases of resistant RCC. 

Next steps for this research include the evaluation of the Hsp70 inhibitor alone and in combination with belzutifan in patient-derived xenograft models of clear cell RCC. In addition to potentially enhanced efficacy, the combination of these agents could also help reduce toxicities observed with molecular chaperone inhibitors, Basin concludes.