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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Female
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Gene Amplification / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 2 / antagonists & inhibitors
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Male
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins p21(ras) / genetics*
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Withholding Treatment
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Zinc Finger E-box-Binding Homeobox 1 / metabolism
Substances
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AZD 6244
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Antineoplastic Agents
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Benzimidazoles
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KRAS protein, human
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Protein Kinase Inhibitors
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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MAP2K2 protein, human
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAPK1 protein, human
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MAPK3 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Proto-Oncogene Proteins p21(ras)