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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2019. "MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance," Nature Communications, Nature, vol. 10(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09438-w
    DOI: 10.1038/s41467-019-09438-w
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