TY - JOUR
T1 - Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors
T2 - Targeting Genetically Driven Tumor Hypoxia
AU - Toledo, Rodrigo A.
AU - Jimenez, Camilo
AU - Armaiz-Pena, Gustavo
AU - Arenillas, Carlota
AU - Capdevila, Jaume
AU - Dahia, Patricia L.M.
N1 - Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel–Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.
AB - Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel–Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.
KW - HIF2
KW - VHL
KW - belzutifan
KW - cancer
KW - hypoxia
KW - hypoxia-inducible factor
KW - inhibitor
KW - mutation
KW - neuroendocrine tumor
KW - paraganglioma
KW - pheochromocytoma
KW - pseudohypoxia
KW - resistance
KW - sensitivity
KW - targeted therapy
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UR - http://www.scopus.com/inward/citedby.url?scp=85149144010&partnerID=8YFLogxK
U2 - 10.1210/endrev/bnac025
DO - 10.1210/endrev/bnac025
M3 - Review article
C2 - 36301191
AN - SCOPUS:85149144010
SN - 0163-769X
VL - 44
SP - 312
EP - 322
JO - Endocrine Reviews
JF - Endocrine Reviews
IS - 2
ER -