Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Rev Urol. 2024 Nov;21(11):662-675. doi: 10.1038/s41585-024-00876-w. Epub 2024 May 2.
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.
肾脏癌细胞适应氧稳态的独特病理和分子特征使其成为研究缺氧信号转导和潜在开发有效靶向治疗方法的理想模型。缺氧信号转导在肾癌中具有关键作用，特别是在最常见的亚型肾透明细胞癌（ccRCC）中。缺氧促进多种关键病理过程，如缺氧诱导因子（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、生长或转移形成。相当一部分肾癌，特别是透明细胞肾细胞癌（ccRCC），由于 von Hippel-Lindau 肿瘤抑制因子（VHL）的功能丧失，导致 HIF 蛋白，特别是 HIF2α的积累，这是 ccRCC 的关键驱动因素。因此，针对 pVHL-HIF 信号的治疗策略已在 ccRCC 中进行了探索，最终成功开发了 HIF2α 特异性拮抗剂，如 belzutifan（PT2977），这是一种 FDA 批准的用于治疗 VHL 相关疾病（包括晚期 ccRCC）的药物。对肾脏癌细胞缺氧信号转导的深入了解来自于对新型 VHL 蛋白（pVHL）靶点的发现，以及与 VHL 突变的合成致死机制。这些突破为开发创新有效的肾癌联合治疗铺平了道路。
