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Sale et al. Cancer Drug Resist 2019;2:365-80 Cancer
DOI: 10.20517/cdr.2019.14 Drug Resistance

Commentary Open Access

Resistance to ERK1/2 pathway inhibitors; sweet
spots, fitness deficits and drug addiction

Matthew J. Sale, Kathryn Balmanno, Simon J. Cook

Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Correspondence to: Drs. Matthew J. Sale, Kathryn Balmanno and Simon J. Cook, Signalling Programme, The Babraham Institute,
Babraham Research Campus, Cambridge CB22 3AT, UK. E-mail: matthew.sale@babraham.ac.uk;
kathy.balmanno@babraham.ac.uk; simon.cook@babraham.ac.uk

How to cite this article: Sale MJ, Balmanno K, Cook SJ. Resistance to ERK1/2 pathway inhibitors; sweet spots, fitness deficits and
drug addiction. Cancer Drug Resist 2019;2:365-80. http://dx.doi.org/10.20517/cdr.2019.14

Received: 12 Mar 2019 First Decision: 5 May 2019 Revised: 8 May 2019 Accepted: 10 May 2019 Published: 19 Jun 2019

Science Editor: Martin Michaelis Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma, where they are used in
combination with BRAF inhibitors, and are undergoing evaluation in other malignancies. Acquired resistance to
MEK1/2 inhibitors, including selumetinib (AZD6244/ARRY-142866), can arise through amplification of BRAF V600E or
KRAS G13D to reinstate ERK1/2 signalling. We have found that BRAF V600E amplification and selumetinib resistance are
fully reversible following drug withdrawal. This is because resistant cells with BRAF V600E amplification become addicted
to selumetinib to maintain a precise level of ERK1/2 signalling (2%-3% of total ERK1/2 active), that is optimal for cell
proliferation and survival. Selumetinib withdrawal drives ERK1/2 activation outside of this critical “sweet spot” (~20%-
30% of ERK1/2 active) resulting in a p57 KIP2 -dependent G1 cell cycle arrest and senescence or expression of NOXA
and cell death with features of autophagy; these terminal responses select against cells with amplified BRAF V600E .
ERK1/2-dependent p57 KIP2 expression is required for loss of BRAF V600E amplification and determines the rate of reversal
of selumetinib resistance. Growth of selumetinib-resistant cells with BRAF V600E amplification as tumour xenografts also
requires the presence of selumetinib to “clamp” ERK1/2 activity within the sweet spot. Thus, BRAF V600E amplification
confers a selective disadvantage or “fitness deficit” during drug withdrawal, providing a rationale for intermittent
dosing to forestall resistance. Remarkably, selumetinib resistance driven by KRAS G13D amplification/upregulation is
not reversible. In these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-
to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy agents.
Our results reveal that the emergence of drug-addicted, MEKi-resistant cells, and the opportunity this may afford for
intermittent dosing schedules (“drug holidays”), may be determined by the nature of the amplified driving oncogene
(BRAF V600E vs. KRAS G13D ), further exemplifying the difficulties of targeting KRAS mutant tumour cells.

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
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