HIF-2 is arguably the most important driver of renal cancer; however, as a transcription factor, HIF-2 has been regarded as undruggable. Courtney and colleagues report a translational companion study to a first-in-class, first-in-human clinical trial of a HIF-2a inhibitor (PT2385) in patients with clear cell renal cell carcinoma (ccRCC). PT2385 inhibited HIF-2 in nontumor as well as tumor tissues, leading to the dissociation of HIF-2 (but not HIF-1) complexes and the inhibition of target genes. A resistance gatekeeper mutation was identified in HIF-2a, which not only validates HIF-2a as the drug target, but also reveals a fundamental core dependency on HIF-2 for tumorigenesis.

Uveal melanoma (UM) is a rare subset of all melanomas with particularly poor outcomes in the metastatic setting. Primary UM overexpresses MET kinase, with preclinical studies suggesting potential efficacy of MET blockade. Cabozantinib is a MET/VEGFR2 kinase inhibitor and a randomized discontinuation phase I study of cabozantinib...

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