MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF amplification but promotes EMT/chemoresistance when KRAS is amplified

Matthew Sale, Kathryn Balmanno, Jayeta Saxena, Eiko Ozono, Katarzyna Wojdyla, Rebecca E McIntyre, Rebecca Gilley, Anne Woroniuk, Karen Howarth, Gareth Hughes, Jonathan Dry, Mark Arends, Pilar Caro, David Oxley, Susan Ashton, David Adams, Julio Saez-Rodriguez, Paul Smith, Simon Cook

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 KRAS amplification.
Original languageEnglish
JournalNature Communications
DOIs
Publication statusPublished - 2 May 2019

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