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

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 RNAsequencing 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).

HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

“…GAGE analyses also identified a significant downregulation of the gene set HIF-2α Transcription Network, including Epo , Egln1 , Egln3 , Igfbp1, and Pfkfb3 . To further investigate potential overlap with recently defined HIF-2α-dependent genes in human ccRCC, we used a set of 277 genes that were identified as being inhibited specifically in tumour cells in ccRCC tumorgrafts in mice treated with the HIF-2α inhibitor PT2399 25 , 35 . Analyses of the expression levels of the mouse orthologues of this set of HIF-2α target genes revealed that many of these genes are highly upregulated in Vhl ∆/∆ Trp53 ∆/∆ Rb1 ∆/∆ tumours compared to WT cortex, but that the loss of either HIF-1α or HIF-2α did not broadly affect the upregulation of these genes (Supplementary Fig.…”

Molecular Crosstalk Between MYC and HIF in Cancer

“…As in other targeted therapy, therapeutic resistance is of a concern. For example, a gatekeeper mutation G323E in HIF-2α was identified to be responsible for PT2385 resistance after prolonged treatment (Courtney et al, 2020). Thus, further insights into the understanding of the MYC-HIF interplay are warranted for developing novel targeted therapeutics.…”

“…PT2385 also inhibited HIF-2α-driven gene expression and induced ccRCC tumor regression (Wallace et al, 2016). Recent result from a phase I clinic trial showed response, partial response or stable disease in ∼66% of patients with favorable safety profile and well tolerance for PT2385 (Courtney et al, 2018(Courtney et al, , 2020. Phase II clinic trials for PT2385 are ongoing in ccRCC (NCT03108066) and recurrent glioblastoma (NCT03216499).…”

Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

“…Understanding the transcriptional regulation by HIFs has provided therapeutic targets currently under clinical evaluation 194,195 . Notably, HIF-2α inhibitors are being tested in renal cell carcinoma and pharmacologic inhibition of PHDs is being explored for the treatment of anaemia 196,197 . However, as conveyed in this article, cellular responses to hypoxia go much beyond the transcriptional networks governed by HIFs.…”