Nature Communications (May 2019)
MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
- 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
Affiliations
- Matthew J. Sale
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Kathryn Balmanno
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Jayeta Saxena
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Eiko Ozono
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Katarzyna Wojdyla
- Proteomics Facility, The Babraham Institute, Babraham Research Campus
- Rebecca E. McIntyre
- Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Genome Campus
- Rebecca Gilley
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Anna Woroniuk
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- Karen D. Howarth
- Hutchison-MRC Research Centre, Department of Pathology, University of Cambridge
- Gareth Hughes
- Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, CRUK Cambridge Institute
- Jonathan R. Dry
- Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca
- Mark J. Arends
- Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital
- Pilar Caro
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- David Oxley
- Proteomics Facility, The Babraham Institute, Babraham Research Campus
- Susan Ashton
- Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca
- David J. Adams
- Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Genome Campus
- Julio Saez-Rodriguez
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI)
- Paul D. Smith
- Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, CRUK Cambridge Institute
- Simon J. Cook
- Signalling Programme, The Babraham Institute, Babraham Research Campus
- DOI
- https://doi.org/10.1038/s41467-019-09438-w
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 1 – 22
Abstract
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.
