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 and Simon J. Cook ()
Additional contact information
Matthew J. Sale: Babraham Research Campus
Kathryn Balmanno: Babraham Research Campus
Jayeta Saxena: Babraham Research Campus
Eiko Ozono: Babraham Research Campus
Katarzyna Wojdyla: Babraham Research Campus
Rebecca E. McIntyre: Wellcome Genome Campus
Rebecca Gilley: Babraham Research Campus
Anna Woroniuk: Babraham Research Campus
Karen D. Howarth: University of Cambridge
Gareth Hughes: CRUK Cambridge Institute
Jonathan R. Dry: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Mark J. Arends: University of Edinburgh, Western General Hospital
Pilar Caro: Babraham Research Campus
David Oxley: Babraham Research Campus
Susan Ashton: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
David J. Adams: Wellcome Genome Campus
Julio Saez-Rodriguez: European Bioinformatics Institute (EMBL-EBI)
Paul D. Smith: CRUK Cambridge Institute
Simon J. Cook: Babraham Research Campus

Nature Communications, 2019, vol. 10, issue 1, 1-22

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09438-w

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