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Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. These precancerous cells contain cancer-associated genomic changes and cause primary tumors and local relapses. Therapeutic strategies to eradicate the...

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Autores principales: van Harten, Anne M., de Boer, D. Vicky, Martens-de Kemp, Sanne R., Buijze, Marijke, Ganzevles, Sonja H., Hunter, Keith D., Leemans, C. René, van Beusechem, Victor W., Wolthuis, Rob M. F., de Menezes, Renée X., Brakenhoff, Ruud H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012863/
https://www.ncbi.nlm.nih.gov/pubmed/32047167
http://dx.doi.org/10.1038/s41598-020-58509-2
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author van Harten, Anne M.
de Boer, D. Vicky
Martens-de Kemp, Sanne R.
Buijze, Marijke
Ganzevles, Sonja H.
Hunter, Keith D.
Leemans, C. René
van Beusechem, Victor W.
Wolthuis, Rob M. F.
de Menezes, Renée X.
Brakenhoff, Ruud H.
author_facet van Harten, Anne M.
de Boer, D. Vicky
Martens-de Kemp, Sanne R.
Buijze, Marijke
Ganzevles, Sonja H.
Hunter, Keith D.
Leemans, C. René
van Beusechem, Victor W.
Wolthuis, Rob M. F.
de Menezes, Renée X.
Brakenhoff, Ruud H.
author_sort van Harten, Anne M.
collection PubMed
description HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. These precancerous cells contain cancer-associated genomic changes and cause primary tumors and local relapses. Therapeutic strategies to eradicate these precancerous cells are very limited. Using functional genomic screens, we identified the therapeutic vulnerabilities of premalignant mucosal cells, which are shared with fully malignant HNSCC cells. We screened 319 previously identified tumor-lethal siRNAs on a panel of cancer and precancerous cell lines as well as primary fibroblasts. In total we identified 147 tumor-essential genes including 34 druggable candidates. Of these 34, 13 were also essential in premalignant cells. We investigated the variable molecular basis of the vulnerabilities in tumor and premalignant cell lines and found indications of collateral lethality. Wee1-like kinase (WEE1) was amongst the most promising targets for both tumor and precancerous cells. All four precancerous cell lines were highly sensitive to Wee1 inhibition by Adavosertib (AZD1775), while primary keratinocytes tolerated this inhibitor. Wee1 inhibition caused induction of DNA damage during S-phase followed by mitotic failure in (pre)cancer cells. In conclusion, we uncovered Wee1 inhibition as a promising chemopreventive strategy for precancerous cells, with comparable responses as fully transformed HNSCC cells.
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spelling pubmed-70128632020-02-21 Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition van Harten, Anne M. de Boer, D. Vicky Martens-de Kemp, Sanne R. Buijze, Marijke Ganzevles, Sonja H. Hunter, Keith D. Leemans, C. René van Beusechem, Victor W. Wolthuis, Rob M. F. de Menezes, Renée X. Brakenhoff, Ruud H. Sci Rep Article HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. These precancerous cells contain cancer-associated genomic changes and cause primary tumors and local relapses. Therapeutic strategies to eradicate these precancerous cells are very limited. Using functional genomic screens, we identified the therapeutic vulnerabilities of premalignant mucosal cells, which are shared with fully malignant HNSCC cells. We screened 319 previously identified tumor-lethal siRNAs on a panel of cancer and precancerous cell lines as well as primary fibroblasts. In total we identified 147 tumor-essential genes including 34 druggable candidates. Of these 34, 13 were also essential in premalignant cells. We investigated the variable molecular basis of the vulnerabilities in tumor and premalignant cell lines and found indications of collateral lethality. Wee1-like kinase (WEE1) was amongst the most promising targets for both tumor and precancerous cells. All four precancerous cell lines were highly sensitive to Wee1 inhibition by Adavosertib (AZD1775), while primary keratinocytes tolerated this inhibitor. Wee1 inhibition caused induction of DNA damage during S-phase followed by mitotic failure in (pre)cancer cells. In conclusion, we uncovered Wee1 inhibition as a promising chemopreventive strategy for precancerous cells, with comparable responses as fully transformed HNSCC cells. Nature Publishing Group UK 2020-02-11 /pmc/articles/PMC7012863/ /pubmed/32047167 http://dx.doi.org/10.1038/s41598-020-58509-2 Text en © The Author(s) 2020 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/.
spellingShingle Article
van Harten, Anne M.
de Boer, D. Vicky
Martens-de Kemp, Sanne R.
Buijze, Marijke
Ganzevles, Sonja H.
Hunter, Keith D.
Leemans, C. René
van Beusechem, Victor W.
Wolthuis, Rob M. F.
de Menezes, Renée X.
Brakenhoff, Ruud H.
Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title_full Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title_fullStr Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title_full_unstemmed Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title_short Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition
title_sort chemopreventive targeted treatment of head and neck precancer by wee1 inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012863/
https://www.ncbi.nlm.nih.gov/pubmed/32047167
http://dx.doi.org/10.1038/s41598-020-58509-2
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