MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance

Colorectal cancer cells can acquire resistance to MEK inhibition due to BRAF or KRAS amplification. Here, the authors show that while MEK inhibitor withdrawal in BRAF mutant cells restores sensitivity to the inhibitor through the loss of BRAF amplification mediated by a p57-dependent mechanism, drug...

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Main Authors:	Matthew J. Sale, Kathryn Balmanno, Jayeta Saxena, Eiko Ozono, Katarzyna Wojdyla, Rebecca E. McIntyre, Rebecca Gilley, Anna Woroniuk, Karen D. Howarth, Gareth Hughes, Jonathan R. Dry, Mark J. Arends, Pilar Caro, David Oxley, Susan Ashton, David J. Adams, Julio Saez-Rodriguez, Paul D. Smith, Simon J. Cook
Format:	Article
Language:	English
Published:	Nature Publishing Group 2019-05-01
Series:	Nature Communications
Online Access:	https://doi.org/10.1038/s41467-019-09438-w

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spelling	doaj-2c81d11afd5f46b09ea78ec188faf5402021-05-11T11:47:16ZengNature Publishing GroupNature Communications2041-17232019-05-0110112210.1038/s41467-019-09438-wMEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistanceMatthew J. Sale0Kathryn Balmanno1Jayeta Saxena2Eiko Ozono3Katarzyna Wojdyla4Rebecca E. McIntyre5Rebecca Gilley6Anna Woroniuk7Karen D. Howarth8Gareth Hughes9Jonathan R. Dry10Mark J. Arends11Pilar Caro12David Oxley13Susan Ashton14David J. Adams15Julio Saez-Rodriguez16Paul D. Smith17Simon J. Cook18Signalling Programme, The Babraham Institute, Babraham Research CampusSignalling Programme, The Babraham Institute, Babraham Research CampusSignalling Programme, The Babraham Institute, Babraham Research CampusSignalling Programme, The Babraham Institute, Babraham Research CampusProteomics Facility, The Babraham Institute, Babraham Research CampusExperimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Genome CampusSignalling Programme, The Babraham Institute, Babraham Research CampusSignalling Programme, The Babraham Institute, Babraham Research CampusHutchison-MRC Research Centre, Department of Pathology, University of CambridgeOncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, CRUK Cambridge InstituteOncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZenecaDivision of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalSignalling Programme, The Babraham Institute, Babraham Research CampusProteomics Facility, The Babraham Institute, Babraham Research CampusOncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZenecaExperimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Genome CampusEuropean Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI)Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, CRUK Cambridge InstituteSignalling Programme, The Babraham Institute, Babraham Research CampusColorectal cancer cells can acquire resistance to MEK inhibition due to BRAF or KRAS amplification. Here, the authors show that while MEK inhibitor withdrawal in BRAF mutant cells restores sensitivity to the inhibitor through the loss of BRAF amplification mediated by a p57-dependent mechanism, drug withdrawal from KRAS mutant cells does not restore sensitivity but results in EMT and chemoresistance.https://doi.org/10.1038/s41467-019-09438-w
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Matthew J. Sale Kathryn Balmanno Jayeta Saxena Eiko Ozono Katarzyna Wojdyla Rebecca E. McIntyre Rebecca Gilley Anna Woroniuk Karen D. Howarth Gareth Hughes Jonathan R. Dry Mark J. Arends Pilar Caro David Oxley Susan Ashton David J. Adams Julio Saez-Rodriguez Paul D. Smith Simon J. Cook
spellingShingle	Matthew J. Sale Kathryn Balmanno Jayeta Saxena Eiko Ozono Katarzyna Wojdyla Rebecca E. McIntyre Rebecca Gilley Anna Woroniuk Karen D. Howarth Gareth Hughes Jonathan R. Dry Mark J. Arends Pilar Caro David Oxley Susan Ashton David J. Adams Julio Saez-Rodriguez Paul D. Smith Simon J. Cook MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance Nature Communications
author_facet	Matthew J. Sale Kathryn Balmanno Jayeta Saxena Eiko Ozono Katarzyna Wojdyla Rebecca E. McIntyre Rebecca Gilley Anna Woroniuk Karen D. Howarth Gareth Hughes Jonathan R. Dry Mark J. Arends Pilar Caro David Oxley Susan Ashton David J. Adams Julio Saez-Rodriguez Paul D. Smith Simon J. Cook
author_sort	Matthew J. Sale
title	MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
title_short	MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
title_full	MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
title_fullStr	MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
title_full_unstemmed	MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
title_sort	mek1/2 inhibitor withdrawal reverses acquired resistance driven by brafv600e amplification whereas krasg13d amplification promotes emt-chemoresistance
publisher	Nature Publishing Group
series	Nature Communications
issn	2041-1723
publishDate	2019-05-01
description	Colorectal cancer cells can acquire resistance to MEK inhibition due to BRAF or KRAS amplification. Here, the authors show that while MEK inhibitor withdrawal in BRAF mutant cells restores sensitivity to the inhibitor through the loss of BRAF amplification mediated by a p57-dependent mechanism, drug withdrawal from KRAS mutant cells does not restore sensitivity but results in EMT and chemoresistance.
url	https://doi.org/10.1038/s41467-019-09438-w
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MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance

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