HIF-2–Dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear-Cell Renal Cell Carcinoma

Abstract Patients with renal cell carcinoma (RCC) and hypercalcemia (HC) have worse outcomes. HC often involves parathyroid hormone–related protein (PTHrP), and the role of hypoxia-inducible factor 2 (HIF-2) is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell–autonomous inflammatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP, and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2–dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including the EPO locus in a TG with paraneoplastic polycythemia). As in TGs, paraneoplastic HC in patients was associated with clear-cell (cc)RCC (and sarcomatoid/rhabdoid differentiation) and was rapidly corrected by PT2977/belzutifan, which unlike bisphosphonates downregulated PTHrP. Our data support evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker. Significance: This study uncovers a direct role for HIF-2 in driving humoral HC of malignancy in ccRCC through transcriptional activation of PTHLH (encoding PTHrP), identifies HC (and PTHrP) as potentially predictive biomarkers of HIF-2 engagement, and sets a foundation for the evaluation of HIF-2 antagonists for HC management in patients.