HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor in Clear Cell Renal Cell Carcinoma Patients.

PURPOSE: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). While considered undruggable, structural analyses at UT Southwestern Medical Center (UTSW) identified a vulnerability in the a subunit, which heterodimerizes with HIF-1b, 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 extensively pretreated ccRCC patients at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control greater than or equal to 4 months was achieved in 42% of patients. EXPERIMENTAL DESIGN: We conducted a prospective companion sub-study 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 magnetic resonance imaging, blood draws and serial biopsies for biochemical, whole exome, and RNA-Seq studies. RESULTS: PT2385 inhibited HIF-2 in non-tumor 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), 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.