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 the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.

中文翻译：

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缺氧诱导因子 2 α (HIF2α) 抑制剂：靶向基因驱动的肿瘤缺氧。

由参与缺氧诱导因子亚基 2 α (HIF2α) 降解的 VHL 基因产物缺陷引起的肿瘤是靶向抑制该通路的天然候选者。Belzutifan 是一种高度特异性且耐受性良好的 HIF2α 抑制剂，最近获得 FDA 批准用于治疗携带 VHL 种系突变的 von Hippel-Lindau 病患者的非转移性肾细胞癌、胰腺神经内分泌肿瘤和中枢神经系统血管母细胞瘤。这种批准是肿瘤学的一个里程碑；然而，临床上 HIF2α 抑制的全部潜力和局限性才刚刚开始被探索。在这里，我们简要概括了肿瘤中 HIF2α 阻断的分子原理，并回顾了可用的临床前和临床数据，详细说明可能对这种方法特别敏感的突变。我们还概述了一些新出现的对 HIF2α 抑制剂的内在和获得性耐药机制，包括 HIF2α 看门人口袋及其相互作用伙伴 ARNT 的获得性突变。最后，我们提出，在由 VHL 突变引起的基因驱动的缺氧肿瘤中观察到的贝尔祖替芬的高效性表明关注其他类似导致 HIF2α 稳定的突变，例如发生在三羧酸循环中断的神经内分泌肿瘤中的突变（ SDHA/B/C/D、FH、MDH2、IDH2）、HIF 羟化酶（EGLN/PHD）和 HIF2α 编码基因 EPAS1 是有保证的。包括 HIF2α 及其相互作用伙伴 ARNT 的守门人口袋的获得性突变。最后，我们提出，在由 VHL 突变引起的基因驱动的缺氧肿瘤中观察到的贝尔祖替芬的高效性表明关注其他类似导致 HIF2α 稳定的突变，例如发生在三羧酸循环中断的神经内分泌肿瘤中的突变（ SDHA/B/C/D、FH、MDH2、IDH2）、HIF 羟化酶（EGLN/PHD）和 HIF2α 编码基因 EPAS1 是有保证的。包括 HIF2α 及其相互作用伙伴 ARNT 的守门人口袋的获得性突变。最后，我们提出，在由 VHL 突变引起的基因驱动的缺氧肿瘤中观察到的贝尔祖替芬的高效性表明关注其他类似导致 HIF2α 稳定的突变，例如发生在三羧酸循环中断的神经内分泌肿瘤中的突变（ SDHA/B/C/D、FH、MDH2、IDH2）、HIF 羟化酶（EGLN/PHD）和 HIF2α 编码基因 EPAS1 是有保证的。