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您的检索式：作者名="Simon J.Cook"
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| 1 | V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a显示文摘 | Linda A. S.Carragher Kimberley R.Snell Susan M.Giblett Victoria S. S.Aldridge BipinPatel Simon J.Cook Doug J.Winton RichardMarais Catrin A.Pritchard | 2010 | EMBO Mol Med2010，，： | 1 |
| 2 | Resistance to ERK1/2 pathway inhibitors;sweet spots,fitness deficits and drug addiction显示文摘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. | Matthew J.Sale Kathryn Balmanno Simon J.Cook | 2019 | Cancer Drug Resistance2019，2，2： | 0 |
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