Targeting Renal Cell Carcinoma with a HIF-2 antagonist
Menée sur des modèles précliniques de carcinome rénal à cellules claires et sur un patient, ces deux études mettent en évidence des mécanismes d'activité antitumorale d'un composé appelé PT2399, un inhibiteur du facteur de transcription HIF-2alpha
Clear cell Renal Cell Carcinoma (ccRCC) is characterized by VHL inactivation. Because no other gene is mutated as frequently, and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates HIF-2, and constitutive HIF-2 restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 is implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs like sunitinib. HIF-2, a transcription factor, has been regarded as undruggable. A structure-based design approach identified a selective HIF-2 antagonist (PT2399) that we evaluate using a tumorgraft (TG)/PDX platform. PT2399 dissociated HIF-2 (an obligatory heterodimer [HIF-2α/HIF-1β])14 in human ccRCC suppressing tumorigenesis in 56% (10/18) lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumors, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant. Resistance occurred despite HIF-2 dissociation in tumors and evidence of Hif-2 inhibition in the mouse as determined by suppression of circulating erythropoietin, a HIF-2 target15 and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumors. Illustrating drug specificity, gene expression was largely unaffected by PT2399 in resistant tumors. Sensitive tumors exhibited a distinguishing gene expression signature, and generally higher HIF-2α levels. Prolonged PT2399 treatment led to resistance. We identified a binding site and second site suppressor mutation in HIF-2α and HIF-1β respectively. Both mutations preserved HIF-2 dimers despite PT2399. Finally, an extensively pretreated patient with a sensitive TG had disease control for >11 months with the close analogue PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCC are, unexpectedly, HIF-2 independent, and set the stage for biomarker-driven clinical trials.
Nature , résumé, 2015