PURPOSE The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

中文翻译：

---

透明细胞肾细胞癌患者中HIF-2复合物的解离，靶标抑制和PT2385（一流的HIF-2抑制剂）获得的耐药性。

目的异二聚体转录因子HIF-2可以说是透明细胞肾细胞癌（ccRCC）的最重要驱动因素。德克萨斯大学西南医学中心（UTSW，德克萨斯州达拉斯）进行的结构分析虽然被认为是不可抗药的，但它发现了α亚基中的一个弱点，该弱点与HIF1β异源二聚体，最终导致了一流抑制剂PT2385的开发。PT2385在UTSW和其他地方经过广泛预处理的ccRCC的患者的首次人类I期临床试验中是安全有效的。没有剂量限制性毒性，并且42％的患者达到了≥4个月的疾病控制。病人和方法我们进行了一项前瞻性附属研究，涉及参加UTSW的I期临床试验的一部分患者（n = 10），他们接受了II期或更高剂量的治疗，涉及多参数MRI，抽血和系列活检，用于生化，全外显子组和RNA测序研究。结果PT2385在非肿瘤组织中抑制了HIF-2，这是由除药物浓度最低的所有患者以外的所有患者中促红细胞生成素水平的降低（一种药效学标志物）所确定的。PT2385在ccRCC转移中解离了HIF-2复合物，并抑制了HIF-2靶基因的表达。相反，HIF-1复合物不受影响。长时间的PT2385治疗导致耐药性的获得，并且我们在HIF2α中鉴定了一个网守突变（G323E），这会干扰药物结合并阻止HIF-2复合物的解离。此外，我们在其他地方发现了获得性TP53突变，表明可能存在耐药性的替代机制。结论这些发现证明了转移性ccRCC中对HIF-2的核心依赖性，并确立了PT2385作为人类中高度特异性的HIF-2抑制剂。将需要新的方法来靶向超过PT2385或密切相关的PT2977（MK-6482）的突变HIF-2。