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RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options th...

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Autores principales: Gudiño, Victoria, Pohl, Sebastian Öther-Gee, Billard, Caroline V., Cammareri, Patrizia, Bolado, Alfonso, Aitken, Stuart, Stevenson, David, Hall, Adam E., Agostino, Mark, Cassidy, John, Nixon, Colin, von Kriegsheim, Alex, Freile, Paz, Popplewell, Linda, Dickson, George, Murphy, Laura, Wheeler, Ann, Dunlop, Malcolm, Din, Farhat, Strathdee, Douglas, Sansom, Owen J., Myant, Kevin B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058071/
https://www.ncbi.nlm.nih.gov/pubmed/33879799
http://dx.doi.org/10.1038/s41467-021-22531-3
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author Gudiño, Victoria
Pohl, Sebastian Öther-Gee
Billard, Caroline V.
Cammareri, Patrizia
Bolado, Alfonso
Aitken, Stuart
Stevenson, David
Hall, Adam E.
Agostino, Mark
Cassidy, John
Nixon, Colin
von Kriegsheim, Alex
Freile, Paz
Popplewell, Linda
Dickson, George
Murphy, Laura
Wheeler, Ann
Dunlop, Malcolm
Din, Farhat
Strathdee, Douglas
Sansom, Owen J.
Myant, Kevin B.
author_facet Gudiño, Victoria
Pohl, Sebastian Öther-Gee
Billard, Caroline V.
Cammareri, Patrizia
Bolado, Alfonso
Aitken, Stuart
Stevenson, David
Hall, Adam E.
Agostino, Mark
Cassidy, John
Nixon, Colin
von Kriegsheim, Alex
Freile, Paz
Popplewell, Linda
Dickson, George
Murphy, Laura
Wheeler, Ann
Dunlop, Malcolm
Din, Farhat
Strathdee, Douglas
Sansom, Owen J.
Myant, Kevin B.
author_sort Gudiño, Victoria
collection PubMed
description Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.
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spelling pubmed-80580712021-05-11 RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways Gudiño, Victoria Pohl, Sebastian Öther-Gee Billard, Caroline V. Cammareri, Patrizia Bolado, Alfonso Aitken, Stuart Stevenson, David Hall, Adam E. Agostino, Mark Cassidy, John Nixon, Colin von Kriegsheim, Alex Freile, Paz Popplewell, Linda Dickson, George Murphy, Laura Wheeler, Ann Dunlop, Malcolm Din, Farhat Strathdee, Douglas Sansom, Owen J. Myant, Kevin B. Nat Commun Article Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer. Nature Publishing Group UK 2021-04-20 /pmc/articles/PMC8058071/ /pubmed/33879799 http://dx.doi.org/10.1038/s41467-021-22531-3 Text en © The Author(s) 2021 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 Article
Gudiño, Victoria
Pohl, Sebastian Öther-Gee
Billard, Caroline V.
Cammareri, Patrizia
Bolado, Alfonso
Aitken, Stuart
Stevenson, David
Hall, Adam E.
Agostino, Mark
Cassidy, John
Nixon, Colin
von Kriegsheim, Alex
Freile, Paz
Popplewell, Linda
Dickson, George
Murphy, Laura
Wheeler, Ann
Dunlop, Malcolm
Din, Farhat
Strathdee, Douglas
Sansom, Owen J.
Myant, Kevin B.
RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title_full RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title_fullStr RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title_full_unstemmed RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title_short RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
title_sort rac1b modulates intestinal tumourigenesis via modulation of wnt and egfr signalling pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058071/
https://www.ncbi.nlm.nih.gov/pubmed/33879799
http://dx.doi.org/10.1038/s41467-021-22531-3
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