由于VHL基因产物缺陷驱动的肿瘤（该基因参与低氧诱导因子亚单位2α（HIF2α）的降解）是该途径靶向抑制的自然候选者。 Belzutifan是一种高度专一且耐受性良好的HIF2α抑制剂，最近获得FDA批准，用于治疗非转移性肾细胞癌、胰腺神经内分泌肿瘤和患有von Hippel Lindau病的中枢神经系统血管母细胞瘤的患者，这些患者携带VHL无性系突变。这种批准标志着肿瘤学上的一个里程碑; 然而，在临床上，HIF2α抑制的全部潜力和限制才刚刚开始探索。在这里，我们简要回顾了在肿瘤中阻断HIF2α的分子基础，并回顾了可用的临床前和临床数据，阐述了可能对这种方法特别敏感的突变。我们还概述了一些内在和获得性对HIF2α抑制剂的耐药机制，包括HIF2α门卫口和其相互作用伙伴ARNT的获得性突变。最后，我们提出Belzutifan在由VHL突变引起的遗传性低氧引起的肿瘤中表现出的高效性表明，重点关注其他类似导致HIF2α稳定的突变，例如在三羧酸循环（TCA）循环中发生干扰的神经内分泌肿瘤中发生的突变（SDHA / B / C / D，FH，MDH2，IDH2），HIF羟化酶（EGLN / PHDs ）和编码HIF2α的基因EPAS1。©作者（S）2022。由牛津大学出版社代表内分泌学会出版。版权所有。 如需权限，请发送电子邮件至：journals.permissions@oup.com。

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner, ARNT. Lastly, we propose that the high efficacy of Belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in tricarboxylic acid cycle (TCA) cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs) and the HIF2α-encoding gene, EPAS1, are warranted.© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.