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

doi:10.1038/s41467-019-09438-w

MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF^V600E amplification whereas KRAS^G13D amplification promotes EMT-chemoresistance

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

Authors

Matthew J Sale¹, Kathryn Balmanno², Jayeta Saxena², Eiko Ozono², Katarzyna Wojdyla³, Rebecca E McIntyre⁴, Rebecca Gilley², Anna Woroniuk², Karen D Howarth⁵, Gareth Hughes⁶, Jonathan R Dry⁷, Mark J Arends⁸, Pilar Caro², David Oxley³, Susan Ashton⁹, David J Adams⁴, Julio Saez-Rodriguez¹⁰, Paul D Smith⁶, Simon J Cook¹¹

Affiliations

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 BRAF^V600E or KRAS^G13D to reinstate ERK1/2 signalling. Here we show that BRAF^V600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAF^V600E 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 p57^KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAF^V600E. p57^KIP2 expression is required for loss of BRAF^V600E amplification and reversal of MEKi resistance. Thus, BRAF^V600E amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRAS^G13D 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^G13D amplification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Benzimidazoles / pharmacology
Benzimidazoles / therapeutic use
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics
Female
Gene Amplification / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 2 / antagonists & inhibitors
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / genetics
Male
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Neoplasms / drug therapy*
Neoplasms / genetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins p21(ras) / genetics*
Withholding Treatment
Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

AZD 6244
Antineoplastic Agents
Benzimidazoles
KRAS protein, human
Protein Kinase Inhibitors
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
MAP2K2 protein, human
BRAF protein, human
Proto-Oncogene Proteins B-raf
MAPK1 protein, human
MAPK3 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding