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

  • Cancer Discov. 2025 Oct 9. doi: 10.1158/2159-8290.CD-25-0638.
Arijit Mal  1 ,  Bingqing Xie  1 ,  Zane Gray  1 ,  Charlotte Small  1 ,  Susmita G Ramanand  2 ,  Yunpeng Gao  2 ,  Vanina Toffessi Tcheuyap  2 ,  Sashi Debnath  1 ,  Alana Christie  2 ,  Jeffrey Miyata  1 ,  Brooklyn Jackson  1 ,  Hua Zhong  2 ,  Boning Gao  3 ,  Jay Lohrey  1 ,  Naim M Maalouf  1 ,  Sangeetha M Reddy  2 ,  John D Minna  1 ,  Ivan Pedrosa  4 ,  Xiankai Sun  5 ,  Ram S Mani  6 ,  Payal Kapur  1 ,  James Brugarolas  1
Affiliations
  • 1. The University of Texas Southwestern Medical Center, Dallas, Texas, United States.
  • 2. The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • 3. The University of Texas Southwestern Medical Center, dallas, TX, United States.
  • 4. The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 5. UT Southwestern Medical Center, Dallas, Texas, United States.
  • 6. The University of Texas Southwestern Medical Center, Dallas, United States.
PMID: 41065553 DOI: 10.1158/2159-8290.CD-25-0638
Abstract

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/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 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 supports evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker.

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