Hsp70 Inhibition Could Help Overcome Belzutifan Resistance in VHL Disease–Associated ccRCC

Treatment with an Hsp70 inhibitor could be used to overcome resistance to belzutifan (Welireg) in patients with von Hippel-Lindau (VHL) disease–associated clear cell renal cell carcinoma (ccRCC), according to data from a preclinical study presented at the 2023 American Urologic Association (AUA) Annual Meeting.¹

Belzutifan, which was approved by the FDA in 2021 for patients for the treatment of adult patients with VHL disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery, was found to cause proteasomal degradation of wild-type HIF2α, but not of resistant mutants.^1,2 Data from the preclinical study demonstrated that HIF2α stability relies on the molecular chaperone Hsp70.

Investigators measured HIF2α levels in 786-0, A498, and 769-P VHL-null ccRCC cell lines treated with belzutifan. HIF2α S304M and G323E mutations had been previously associated with belzutifan resistance, and treating ccRCC cells with Hsp70 inhibitor JG-98 led to mutant-HIF2α degradation to overcome belzutifan resistance.

“We found that [S304M and G323E] mutations were not susceptible to belzutifan, which is a HIF2α inhibitor. However, Hsp70 is a molecular chaperone [for] HIF2α, and by targeting Hsp70 with an inhibitor, we were able to decrease the levels of HIF2α, which is known to drive tumor cell growth in ccRCC,” lead study author Michael Basin, MD, said.

In an interview with OncLive®, Basin, discussed the rationale for the preclinical investigation of belzutifan resistance in ccRCC cell lines, the next steps for this research, and the potential implications for combining Hsp70 inhibition with a HIF2α inhibitor. Basin is a resident at the State University of New York Upstate University Hospital, Upstate Medical University, in Syracuse, New York.

OncLive: Can you describe the rationale for investigating the resistance of belzutifan in patients with VHL-associated ccRCC?

Basin: There have been many new medications that have come out for [patients with] kidney cancer in the past 5 to 10 years in terms of systemic agents. While some tumors do respond [to these treatments], others do not. [Therefore], we took belzutifan, which was approved [in 2021] for patients with ccRCC [with associated VHL disease].

Although prior studies have demonstrated that some tumors do respond to [belzutifan], other tumors are inherently resistant, and even those that do initially respond develop resistance over time. We wanted to [find a way] overcome this resistance to belzutifan, so we thought that targeting a molecular chaperone, such as Hsp70, may be an alternative therapeutic target.

What methods were used in this analysis?

Predominantly, we used cell-based assays and biochemical analysis. We took kidney cancer cell lines that were VHL-null, which are predominantly the ccRCC cell lines, and used those cells. We then used [S304M and G323E] mutations that were previously reported in literature that were known to be resistant to HIF2α inhibition, and then expressed those in various cell lines to target with belzutifan and an Hsp70 inhibitor.

What next steps for this research and the potential implications for these preclinical data?

The next steps would be to look at patient-derived xenografts and [conduct this research] in tissue, as opposed to just cell lines. [Then we need] to find if there is any synergy between belzutifan and Hsp70 [inhibition] together and [see if we can] minimize the toxicity that exists, especially with some of the molecular chaperone inhibition.

What are some of the known adverse effects [AEs] associated with Hsp7- inhibition?

There are a lot [of AEs] in terms of gastrointestinal AEs, liver toxicity, and some ocular issues. When used as a monotherapy, [Hsp70 inhibition] does have significant toxicity, but hopefully when it is done in synergy with another medication, you can reduce the dosages and make it more tolerable.

References

1. Basin M, Backe SJ, Bratslavsky MS, et al. Pharmacological inhibition of the molecular chaperone Hsp70 overcomes belzutifan resistance in ccRCC. Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract MP04-12.
2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed May 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease