ArticleClinical cancer research : an official journal of the American Association for Cancer Research2020
HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers.
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Who cites it
130 citing papers in PubMed, 179 citations in OpenAlex.
- Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.Journal of neuro-oncology · 2023Trial
- Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.The New England journal of medicine · 2021Trial
- Targeting p300/CBP destabilizes HIF-2α and suppresses tumor growth in cell and animal models of clear cell renal cell carcinoma.Cancer letters · 2026Article
- Advancing clinical trials for rare renal cell carcinoma subtypes: Consensus statements from the International Kidney Cancer Symposium North America 2025 think tank.Urologic oncology · 2026Article
- Beyond hypoxia and ccRCC: the expanding universe of VHL novel targets and next-generation therapeutics.Biomarker research · 2026Review
- SET1B Drives Sustained HIF Activity and Disease Progression in Clear-Cell Renal Cell Carcinoma.Cancer research · 2026Article
- Article
- Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment.bioRxiv : the preprint server for biology · 2026Article
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- The CLOCK-BMAL1 complex in circadian regulation: structure, mechanisms, and therapeutic targeting.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.The Journal of clinical investigation · 2026Article
- Depleting HIF‑1α attenuates the progression of osteosarcoma, but tumorigenicity is sustained through HIF‑independent pathways.Oncology reports · 2026Article
- Review
- HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer.Cell reports. Medicine · 2026Article
- <p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>.International journal of oncology · 2026Review
- Rhythms of risk: the intersection of clocks, cancer, and chronotherapy.The Journal of clinical investigation · 2026Review
- Review
- First-in-class HIF-2α therapy in genitourinary oncology: Belzutifan from von Hippel-Lindau disease to advanced renal cell carcinoma.Cancer chemotherapy and pharmacology · 2026Review
- Holocord syringomyelia associated with von Hippel-Lindau disease: a case series.Frontiers in surgery · 2026Article
- Pan-cancer biomarkers of immune therapy resistance: mechanisms and clinical translation.Frontiers in cell and developmental biology · 2026Review
70 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 4 institutions in 1 country.
Funding
Abstract
purposeThe 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
methodsWe conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (
resultsPT2385 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
conclusionsThese 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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.