HIF-2-dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear Cell Renal Cell Carcinoma.

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-10-09 DOI:10.1158/2159-8290.cd-25-0638

Arijit Mal,Bingqing Xie,Zane Gray,Charlotte Small,Susmita G Ramanand,Yunpeng Gao,Vanina Toffessi Tcheuyap,Sashi Debnath,Alana Christie,Jeffrey Miyata,Brooklyn Jackson,Hua Zhong,Boning Gao,Jay Lohrey,Naim M Maalouf,Sangeetha M Reddy,John D Minna,Ivan Pedrosa,Xiankai Sun,Ram S Mani,Payal Kapur,James Brugarolas

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引用次数: 0

Abstract

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a TG with paraneoplastic polycythemia). As in TGs, paraneoplastic HC in patients was associated with clear cell (cc)RCC (and sarcomatoid/rhabdoid differentiation) and was rapidly corrected by PT2977/belzutifan, which unlike bisphosphonates, downregulated PTHrP. Our data supports evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker.

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侵袭性透明细胞肾细胞癌中PTHrP和副肿瘤性高钙血症的hif -2依赖性调节。

肾细胞癌（RCC）合并高钙血症（HC）患者预后较差。HC常涉及PTHrP， HIF-2的作用尚不完全清楚。利用以肿瘤细胞自主炎症/免疫特征为特征的HC的RCC肿瘤移植（TG）模型，我们发现PT2399抑制HIF-2经常使钙正常化，下调循环PTHrP并减少HIF-2与PTHLH （PTHrP）启动子的结合。可能在hif -2依赖性肿瘤的一个亚群中选择性诱导PTHrP， PTHLH位点通常在TG（HC）中更容易获得。然而，PTHLH染色质可及性不受PT2399的影响，不像其他地方（包括副肿瘤性红细胞增多症的TG中的EPO位点）。与TGs一样，患者的副肿瘤HC与透明细胞（cc）RCC（和肉瘤样/横纹肌样分化）相关，并通过PT2977/belzutifan迅速纠正，与双磷酸盐不同，PT2977/belzutifan下调PTHrP。我们的数据支持评估HIF-2拮抗剂对ccRCC伴副肿瘤HC患者的疗效，HIF-2拮抗剂可能作为一种预测性生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.