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Two recent independent studies published in  Nature  show robust responses of clear cell renal cell carcinoma (ccRCC) cell lines, preclinical ccRCC xenograft models and, remarkably, a patient with progressive ccRCC despite receiving multiple lines of treatment, to the long-awaited, recently developed inhibitors of hypoxia-inducible factor 2-alpha (HIF2α). This commentary published in  Endocrine-Related Cancer  is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations have been detected in the von Hippel–Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH) and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2α itself: EPAS1 HIF2α . Importantly, the recent discovery of  EPAS1  mutations in PPGLs and the results of comprehensive  in vitro  and  in vivo  studies revealing their oncogenic roles characterized a hitherto unknown direct mechanism of HIF2α activation in human cancer. The now available therapeutic opportunity to successfully inhibit HIF2α pharmacologically with PT2385 and PT2399 will certainly spearhead a series of investigations in several types of cancers, including patients with  SDHB -related metastatic PPGL for whom limited therapeutic options are currently available. Future studies will determine the efficacy of these promising drugs against the hotspot  EPAS1  mutations affecting HIF2α amino acids 529–532 (in PPGLs) and amino acids 533–540 (in erythrocytosis type 4), as well as against HIF2α protein activated by  VHL ,  SDHx  and  FH  mutations in PPGL-derived chromatin cells.

New HIF2α inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas