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Nat Commun. 2019 May 2;10(1):2030. doi: 10.1038/s41467-019-09438-w.

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

Author information

1
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. matthew.sale@babraham.ac.uk.
2
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
3
Proteomics Facility, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
4
Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
5
Hutchison-MRC Research Centre, Department of Pathology, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, UK.
6
Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
7
Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA.
8
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, Crewe Road South, Edinburgh, EH4 2XR, UK.
9
Oncology Bioscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
10
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
11
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. simon.cook@babraham.ac.uk.

Abstract

Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAFV600E amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAFV600E. p57KIP2 expression is required for loss of BRAFV600E amplification and reversal of MEKi resistance. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRASG13D amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRASG13D amplification.

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