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

Kevin D. Courtney, Yuanqing Ma, Alberto Diaz de Leon, Alana Christie, Zhiqun Xie, Layton Woolford, Nirmish Singla, Allison Joyce, Haley Hill, Ananth J. Madhuranthakam, Qing Yuan, Yin Xi, Yue Zhang, Jenny Chang, Oluwatomilade Fatunde, Yull Arriaga, Arthur E. Frankel, Sanjeeva Kalva, Song Zhang, Tiffani McKenzieOscar Reig Torras, Robert A. Figlin, Brian I. Rini, Renee M. McKay, Payal Kapur, Tao Wang, Ivan Pedrosa, James Brugarolas

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 a subunit, which heterodimerizes with HIF1b, 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 ¼ 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 HIF2a, 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).

Original languageEnglish (US)
Pages (from-to)793-803
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number4
DOIs
StatePublished - Feb 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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