Von Hippel–Lindau protein signalling in clear cell renal cell carcinoma

IF 12.1 1区 医学 Q1 UROLOGY & NEPHROLOGY Nature Reviews Urology Pub Date : 2024-05-02 DOI:10.1038/s41585-024-00876-w
Chengheng Liao, Lianxin Hu, Qing Zhang
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Abstract

The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel–Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL–HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer. In this Review, the authors discuss hypoxia signalling and therapeutic strategies targeting this pathway in renal cell carcinoma, with a specific focus on clear cell renal cell carcinoma, in which hypoxia signalling is primarily driven by Von Hippel–Lindau tumour suppressor (VHL) loss.

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透明细胞肾细胞癌中的 Von Hippel-Lindau 蛋白信号传导
肾癌在适应氧平衡方面具有独特的病理和分子特征,这使得这种恶性肿瘤成为研究缺氧信号传导和潜在开发强效靶向疗法的极具吸引力的模型。缺氧信号在肾癌,尤其是最常见的肾细胞癌(RCC)亚型中起着关键作用。低氧促进了各种关键的病理过程,如低氧诱导因子(HIF)激活、血管生成、增殖、代谢重编程和耐药性,所有这些都有助于肾癌的发展、生长或转移的形成。相当一部分肾癌,尤其是透明细胞 RCC(ccRCC),其特点是 Von Hippel-Lindau 肿瘤抑制因子(VHL)功能缺失,导致 HIF 蛋白,尤其是 HIF2α 的积累,而 HIF2α 是 ccRCC 的关键驱动因子。因此,针对 pVHL-HIF 信号的治疗策略在 ccRCC 中得到了探索,最终成功开发出了 HIF2α 特异性拮抗剂,如美国 FDA 批准用于治疗 VHL 相关疾病(包括晚期 ccRCC)的药物 belzutifan(PT2977)。通过发现新型 VHL 蛋白(pVHL)靶点和 VHL 突变的合成致死机制,人们对肾癌中的缺氧信号有了更深入的了解。这些突破可为开发创新的肾癌强效综合疗法铺平道路。
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来源期刊
Nature Reviews Urology
Nature Reviews Urology 医学-泌尿学与肾脏学
CiteScore
12.50
自引率
2.60%
发文量
123
审稿时长
6-12 weeks
期刊介绍: Nature Reviews Urology is part of the Nature Reviews portfolio of journals.Nature Reviews' basic, translational and clinical content is written by internationally renowned basic and clinical academics and researchers. This journal targeted readers in the biological and medical sciences, from the postgraduate level upwards, aiming to be accessible to professionals in any biological or medical discipline. The journal features authoritative In-depth Reviews providing up-to-date information on topics within a field's history and development. Perspectives, News & Views articles, and the Research Highlights section offer topical discussions and opinions, filtering primary research from various medical journals. Covering a wide range of subjects, including andrology, urologic oncology, and imaging, Nature Reviews provides valuable insights for practitioners, researchers, and academics within urology and related fields.
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