HIF-2-dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear Cell Renal Cell Carcinoma [ATAC-seq]

Hypercalcemia (HC) in renal cell carcinoma (RCC) patients is associated with reduced survival. HC often involves PTHrP. PTHrP is induced by hypoxia, but whether HIF-2 plays a role in HC is unknown. Here we show that HC is reproduced by transplanting patient tumors (tumorgrafts, TG) in mice resulting in functional deterioration, weight loss, calcium deposition and organ damage. Treatment with PT2399, a specific HIF-2 inhibitor, rapidly normalized calcium levels, downregulated PTHrP and reduced HIF-2 binding to the PTHLH promoter. Interestingly, while the PTHLH locus was generally more accessible in TG(HC), PT2399 did not grossly affect chromatin accessibility, which was consistent with genome-wide studies where promoter accessibility was only reduced in a minority of PT2399-downregulated genes. As in TGs, paraneoplastic HC in humans was associated with clear cell histology and sarcomatoid/rhabdoid differentiation. Interestingly, HC (and PTHrP) was swiftly corrected by the related PT2977/belzutifan drug in a prospective patient with sarcomatoid ccRCC. Our data supports the evaluation of HIF-2 antagonists for ccRCC patients with humoral hypercalcemia of malignancy, which may serve as a predictive biomarker of response (along with PTHrP reduction).