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WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer
Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt‐addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033517/ https://www.ncbi.nlm.nih.gov/pubmed/33660437 http://dx.doi.org/10.15252/emmm.202013349 |
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author | Kaur, Amanpreet Lim, Jun Yi Stanley Sepramaniam, Sugunavathi Patnaik, Siddhi Harmston, Nathan Lee, May Ann Petretto, Enrico Virshup, David M Madan, Babita |
author_facet | Kaur, Amanpreet Lim, Jun Yi Stanley Sepramaniam, Sugunavathi Patnaik, Siddhi Harmston, Nathan Lee, May Ann Petretto, Enrico Virshup, David M Madan, Babita |
author_sort | Kaur, Amanpreet |
collection | PubMed |
description | Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt‐addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt‐addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51, are dependent on Wnt/β‐catenin signaling in Wnt‐high cancers, and treatment with a PORCN inhibitor creates a BRCA‐like state. This coherent regulation of DNA repair genes occurs in part via a Wnt/β‐catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt‐high APC(min) mutant polyps. Our findings suggest a general paradigm that Wnt/β‐catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents. |
format | Online Article Text |
id | pubmed-8033517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80335172021-04-14 WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer Kaur, Amanpreet Lim, Jun Yi Stanley Sepramaniam, Sugunavathi Patnaik, Siddhi Harmston, Nathan Lee, May Ann Petretto, Enrico Virshup, David M Madan, Babita EMBO Mol Med Articles Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt‐addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt‐addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51, are dependent on Wnt/β‐catenin signaling in Wnt‐high cancers, and treatment with a PORCN inhibitor creates a BRCA‐like state. This coherent regulation of DNA repair genes occurs in part via a Wnt/β‐catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt‐high APC(min) mutant polyps. Our findings suggest a general paradigm that Wnt/β‐catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents. John Wiley and Sons Inc. 2021-03-04 2021-04-09 /pmc/articles/PMC8033517/ /pubmed/33660437 http://dx.doi.org/10.15252/emmm.202013349 Text en © 2021 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Kaur, Amanpreet Lim, Jun Yi Stanley Sepramaniam, Sugunavathi Patnaik, Siddhi Harmston, Nathan Lee, May Ann Petretto, Enrico Virshup, David M Madan, Babita WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title | WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title_full | WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title_fullStr | WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title_full_unstemmed | WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title_short | WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer |
title_sort | wnt inhibition creates a brca‐like state in wnt‐addicted cancer |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033517/ https://www.ncbi.nlm.nih.gov/pubmed/33660437 http://dx.doi.org/10.15252/emmm.202013349 |
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