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

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. Competing Interest Statement M.A-R., N.B., N.H.S, Q.J., M.M, S.M.V, K.E., and N.D.U declare no competing interests. L.A.S. is a shareholder of Blueprint Medicines. E.S. receives research funding from Genentech/imCORE and Oncohost. J.L., H.W., Z.L., and W.S. are employed by NiKang Therapeutics. K.E. is employed by Daiichi Sankyo. T.K.C. reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria in the past five years (ongoing or not) from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Bicycle Therapeutics, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Institut Servier, Ipsen, Jansen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME and non-CME events (Mashup Media Peerview, OncLive, MJH, CCO, and others), outside the submitted work. He has institutional patents filed on molecular alterations and immunotherapy response/toxicity, ctDNA, and rare genitourinary cancers and holds equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium, Abalytics, and Faron Pharma. He serves on committees including NCCN, GU Steering Committee, ASCO (BOD 6-2024-), ESMO, ACCRU, and KidneyCan. Medical writing and editorial assistance support may have been funded in part by communications companies. He has no speakers bureau affiliations and has mentored several non-U.S. citizens on research projects with potential funding (in part) from non-U.S. sources/foreign components. J.R.P. receives research funding from Boehringer-Ingelheim. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer and PrognomIQ. W.G.K. has financial interests in Lilly Pharmaceuticals, Fibrogen, Cedilla Therapeutics, Nextech Invest, Tango Therapeutics, Circle Pharma, IconOVir Bio, Casdin Capital, and LifeMine Therapeutics. He has received consulting income from Arcus Therapeutics and has a royalty interest in the HIF2 inhibitor belzutifan, which is currently being commercialized by Merck.