Journal Article

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

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

2019

Overview

Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF or KRAS to reinstate ERK1/2 signalling. Here we show that BRAF amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAF 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 -dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAF . p57 expression is required for loss of BRAF amplification and reversal of MEKi resistance. Thus, BRAF amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRAS 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.

• Subject: 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 / Male / MAP Kinase Kinase 1 - antagonists & inhibitors / MAP Kinase Kinase 2 - antagonists & inhibitors / MAP Kinase Signaling System - drug effects / MAP Kinase Signaling System - genetics / 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