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Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway

Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is pre...

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Autores principales: Stransky, Laura A., Vigeant, Sean M., Huang, Bofu, West, Destiny, Denize, Thomas, Walton, Emily, Signoretti, Sabina, Kaelin, William G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168943/
https://www.ncbi.nlm.nih.gov/pubmed/35357972
http://dx.doi.org/10.1073/pnas.2120403119
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author Stransky, Laura A.
Vigeant, Sean M.
Huang, Bofu
West, Destiny
Denize, Thomas
Walton, Emily
Signoretti, Sabina
Kaelin, William G.
author_facet Stransky, Laura A.
Vigeant, Sean M.
Huang, Bofu
West, Destiny
Denize, Thomas
Walton, Emily
Signoretti, Sabina
Kaelin, William G.
author_sort Stransky, Laura A.
collection PubMed
description Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is present. The inappropriate accumulation of HIF2 drives tumor formation by VHL tumor suppressor protein (pVHL)–defective ccRCC. Belzutifan, a first-in-class allosteric HIF2 inhibitor, has advanced to phase 3 testing for advanced ccRCC and is approved for ccRCCs arising in patients with VHL disease, which is caused by germline VHL mutations. HIF2 can suppress p53 function in some settings and preliminary data suggested that an intact p53 pathway, as measured by activation in response to DNA damage, was necessary for HIF2 dependence. Here, we correlated HIF2 dependence and p53 status across a broader collection of ccRCC cell lines. We also genetically manipulated p53 function in ccRCC lines that were or were not previously HIF2-dependent and then assessed their subsequent sensitivity to HIF2 ablation using CRISPR-Cas9 or the HIF2 inhibitor PT2399, which is closely related to belzutifan. From these studies, we conclude that p53 status does not dictate HIF2 dependence, at least in preclinical models, and thus is unlikely to be a useful biomarker for predicting which ccRCC patients will respond to HIF2 inhibitors.
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spelling pubmed-91689432022-06-07 Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway Stransky, Laura A. Vigeant, Sean M. Huang, Bofu West, Destiny Denize, Thomas Walton, Emily Signoretti, Sabina Kaelin, William G. Proc Natl Acad Sci U S A Biological Sciences Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is present. The inappropriate accumulation of HIF2 drives tumor formation by VHL tumor suppressor protein (pVHL)–defective ccRCC. Belzutifan, a first-in-class allosteric HIF2 inhibitor, has advanced to phase 3 testing for advanced ccRCC and is approved for ccRCCs arising in patients with VHL disease, which is caused by germline VHL mutations. HIF2 can suppress p53 function in some settings and preliminary data suggested that an intact p53 pathway, as measured by activation in response to DNA damage, was necessary for HIF2 dependence. Here, we correlated HIF2 dependence and p53 status across a broader collection of ccRCC cell lines. We also genetically manipulated p53 function in ccRCC lines that were or were not previously HIF2-dependent and then assessed their subsequent sensitivity to HIF2 ablation using CRISPR-Cas9 or the HIF2 inhibitor PT2399, which is closely related to belzutifan. From these studies, we conclude that p53 status does not dictate HIF2 dependence, at least in preclinical models, and thus is unlikely to be a useful biomarker for predicting which ccRCC patients will respond to HIF2 inhibitors. National Academy of Sciences 2022-03-31 2022-04-05 /pmc/articles/PMC9168943/ /pubmed/35357972 http://dx.doi.org/10.1073/pnas.2120403119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Stransky, Laura A.
Vigeant, Sean M.
Huang, Bofu
West, Destiny
Denize, Thomas
Walton, Emily
Signoretti, Sabina
Kaelin, William G.
Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title_full Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title_fullStr Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title_full_unstemmed Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title_short Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway
title_sort sensitivity of vhl mutant kidney cancers to hif2 inhibitors does not require an intact p53 pathway
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168943/
https://www.ncbi.nlm.nih.gov/pubmed/35357972
http://dx.doi.org/10.1073/pnas.2120403119
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