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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\n                  <jats:italic>PTHLH<\/jats:italic>\n                  , which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. 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 ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.\n                <\/jats:p>","DOI":"10.1101\/2025.09.09.675147","type":"posted-content","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T20:55:13Z","timestamp":1757624113000},"source":"Crossref","is-referenced-by-count":1,"title":["HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors"],"prefix":"10.64898","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"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1633-4389","authenticated-orcid":false,"given":"Nikita","family":"Bhalerao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2579-456X","authenticated-orcid":false,"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8700-9312","authenticated-orcid":false,"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5312-1402","authenticated-orcid":false,"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":"54368","reference":[{"key":"2025091302100882000_2025.09.09.675147v1.1","unstructured":"Cancer Stat Facts: Kidney and Renal Pelvis Cancer. 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