HIF2-driven PTHrP Mediates Cachexia and Hypercalcemia in Renal Cell Carcinoma: Successful Treatment with HIF2 Inhibitors [polysome-seq]
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 NK-2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in patients who did not exhibit objective tumor shrinkage. Overall design: We aim to systematically identify HIF-responsive genes by RNA-Seq in OS-RC-2 cells. We generated two isogenic comparisons to create HIF2 high and low status, for which cells 1) were treated with 2 uM PT2399 (PT) or vehicle (Veh) for 72 hours, 2) underwent CRISPR-based gene editing with a HIF2a sgRNA or a contrl sgRNA (sgCtrl). We then performed RNA-Seq experiments to quantify gene expression for each condition in triplicates.