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Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations

p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA dama...

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Autores principales: Meng, Xiangbing, Gao, Jason Z., Gomendoza, Sean Michael T., Li, John W., Yang, Shujie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520942/
https://www.ncbi.nlm.nih.gov/pubmed/34671620
http://dx.doi.org/10.3389/fmed.2021.737951
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author Meng, Xiangbing
Gao, Jason Z.
Gomendoza, Sean Michael T.
Li, John W.
Yang, Shujie
author_facet Meng, Xiangbing
Gao, Jason Z.
Gomendoza, Sean Michael T.
Li, John W.
Yang, Shujie
author_sort Meng, Xiangbing
collection PubMed
description p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA damage. Tumor cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability and are consequently vulnerable to Wee1 inhibitors, which override the cell cycle G2/M checkpoint and induce cell death through mitotic catastrophe. In addition to the lost tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. In cancer cells with GOF Mutp53, statins can induce CHIP-mediated degradation of Mutp53 within the mevalonate pathway by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of Mutp53 provides an alternative strategy for treating cancers expressing Mutp53. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations.
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spelling pubmed-85209422021-10-19 Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations Meng, Xiangbing Gao, Jason Z. Gomendoza, Sean Michael T. Li, John W. Yang, Shujie Front Med (Lausanne) Medicine p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA damage. Tumor cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability and are consequently vulnerable to Wee1 inhibitors, which override the cell cycle G2/M checkpoint and induce cell death through mitotic catastrophe. In addition to the lost tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. In cancer cells with GOF Mutp53, statins can induce CHIP-mediated degradation of Mutp53 within the mevalonate pathway by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of Mutp53 provides an alternative strategy for treating cancers expressing Mutp53. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations. Frontiers Media S.A. 2021-10-04 /pmc/articles/PMC8520942/ /pubmed/34671620 http://dx.doi.org/10.3389/fmed.2021.737951 Text en Copyright © 2021 Meng, Gao, Gomendoza, Li and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Meng, Xiangbing
Gao, Jason Z.
Gomendoza, Sean Michael T.
Li, John W.
Yang, Shujie
Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title_full Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title_fullStr Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title_full_unstemmed Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title_short Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations
title_sort recent advances of wee1 inhibitors and statins in cancers with p53 mutations
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520942/
https://www.ncbi.nlm.nih.gov/pubmed/34671620
http://dx.doi.org/10.3389/fmed.2021.737951
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