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Further, we show that the increased\n                    <jats:italic>PTHLH<\/jats:italic>\n                    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 patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04054-2","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:01:49Z","timestamp":1764324109000},"page":"245-257","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting of HIF2-driven cachexia in kidney cancer"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4962-3826","authenticated-orcid":false,"given":"Muhannad","family":"Abu-Remaileh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8834-936X","authenticated-orcid":false,"given":"Laura A.","family":"Stransky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Bhalerao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin H.","family":"Shirole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Saad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6708-9922","authenticated-orcid":false,"given":"Marc","family":"Machaalani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean M.","family":"Vigeant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilina","family":"Woldemichael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6210-8699","authenticated-orcid":false,"given":"Kei","family":"Enomoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-3217","authenticated-orcid":false,"given":"Toni K.","family":"Choueiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9549-4768","authenticated-orcid":false,"given":"Jason R.","family":"Pitarresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-4299","authenticated-orcid":false,"given":"Steven A.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namrata D.","family":"Udeshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0574-4856","authenticated-orcid":false,"suffix":"Jr","given":"William G.","family":"Kaelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"4054_CR1","unstructured":"Cancer stat facts: kidney and renal pelvis cancer. 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E.S. receives research funding from Genentech\/imCORE and Oncohost. J.L., H. Wei, 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 5 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 speaker\u2019s bureau affiliations and has mentored several non-US citizens on research projects with potential funding (in part) from non-US 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. Jr 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. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}