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Clinical prospects of WRN inhibition as a treatment for MSI tumours

The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicas...

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Autores principales: Morales-Juarez, David A., Jackson, Stephen P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9666358/
https://www.ncbi.nlm.nih.gov/pubmed/36379964
http://dx.doi.org/10.1038/s41698-022-00319-y
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author Morales-Juarez, David A.
Jackson, Stephen P.
author_facet Morales-Juarez, David A.
Jackson, Stephen P.
author_sort Morales-Juarez, David A.
collection PubMed
description The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicase and tumours with microsatellite instability, a phenotype that arises from DNA mismatch repair deficiency. While these and further studies have highlighted the therapeutic potential of WRN inhibitors, compounds with properties suitable for clinical exploitation remain to be described. Furthermore, the complexities of MSI development and its relationship to cancer evolution pose challenges for clinical prospects. Here, we discuss possible paths of MSI tumour development, the viability of WRN inhibition as a strategy in different scenarios, and the necessary conditions to create a roadmap towards successful implementation of WRN inhibitors in the clinic.
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spelling pubmed-96663582022-11-17 Clinical prospects of WRN inhibition as a treatment for MSI tumours Morales-Juarez, David A. Jackson, Stephen P. NPJ Precis Oncol Perspective The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicase and tumours with microsatellite instability, a phenotype that arises from DNA mismatch repair deficiency. While these and further studies have highlighted the therapeutic potential of WRN inhibitors, compounds with properties suitable for clinical exploitation remain to be described. Furthermore, the complexities of MSI development and its relationship to cancer evolution pose challenges for clinical prospects. Here, we discuss possible paths of MSI tumour development, the viability of WRN inhibition as a strategy in different scenarios, and the necessary conditions to create a roadmap towards successful implementation of WRN inhibitors in the clinic. Nature Publishing Group UK 2022-11-15 /pmc/articles/PMC9666358/ /pubmed/36379964 http://dx.doi.org/10.1038/s41698-022-00319-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Perspective
Morales-Juarez, David A.
Jackson, Stephen P.
Clinical prospects of WRN inhibition as a treatment for MSI tumours
title Clinical prospects of WRN inhibition as a treatment for MSI tumours
title_full Clinical prospects of WRN inhibition as a treatment for MSI tumours
title_fullStr Clinical prospects of WRN inhibition as a treatment for MSI tumours
title_full_unstemmed Clinical prospects of WRN inhibition as a treatment for MSI tumours
title_short Clinical prospects of WRN inhibition as a treatment for MSI tumours
title_sort clinical prospects of wrn inhibition as a treatment for msi tumours
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9666358/
https://www.ncbi.nlm.nih.gov/pubmed/36379964
http://dx.doi.org/10.1038/s41698-022-00319-y
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