HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Muhannad Abu‐Remaileh; Laura A. Stransky; Nikita Bhalerao; Nitin H. Shirole; Qinqin Jiang; Eddy Saad; Marc Machaalani; Sean M. Vigeant; Hilina B. Woldemichael; Charles Xu; Jing Lu; Hairong Wei; Zhihong Liu; William Y. Sun; Kei Enomoto; Toni K. Choueiri; Jason Robert Pitarresi; Steven A. Carr; Namrata D. Udeshi; William G. Kaelin

doi:10.1038/s41591-025-04054-2

Cancer BiologyNature MedicineNov 28, 2025

Peer-reviewed journal article

HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Muhannad Abu‐Remaileh iD, Laura A. Stransky iD, Nikita Bhalerao iD, Nitin H. Shirole iD, Qinqin Jiang iD, Eddy Saad iD, Marc Machaalani iD, Sean M. Vigeant, Hilina B. Woldemichael iD, Charles Xu iD, Jing Lu iD, Hairong Wei iD, Zhihong Liu iD, William Y. Sun iD, Kei Enomoto iD, Toni K. Choueiri iD, Jason Robert Pitarresi iD, Steven A. Carr iD, Namrata D. Udeshi iD, William G. Kaelin iD

Abstract

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma, is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.

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