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

作　　者：Matthew J.Sale Kathryn Balmanno Simon J.Cook 

机构地区：[1]Signalling Programme,The Babraham Institute,Babraham Research Campus,Cambridge CB223AT,UK

出　　处：《Cancer Drug Resistance》2019年第2期365-380,共16页癌症耐药（英文）

基　　金：Work in the Cook laboratory relevant to this article was supported by Cancer Research UK A14867,a Cambridge Cancer Centre PhD Studentship,a BBSRC PhD studentship,to Sale MJ and Cook SJ;an AstraZeneca-Cambridge Cancer Centre Collaborative Award,to Sale MJ and Cook SJ;Institute Strategic Programme(BB/J004456/1,BB/P013384/1)from BBSRC to Balmanno K and Cook SJ,and AstraZeneca.

摘　　要：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 b

关 键 词：BRAF CDKN1C/p57^(KIP2) EMT ERK KRAS MEK MEK inhibitor RESISTANCE SELUMETINIB 

分 类 号：R73[医药卫生—肿瘤]