Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERKI/2 signalling and/or strong P13K signalling in colorectal cancer cell lines

被引:119
作者
Balmanno, Kathryn [1 ]
Chell, Simon D. [1 ]
Gillings, Annette S. [1 ]
Hayat, Shaista [1 ]
Cook, Simon J. [1 ]
机构
[1] Babraham Inst, Mol Signalling Lab, Cambridge CB22 3AT, England
基金
英国生物技术与生命科学研究理事会;
关键词
BRAF; colorectal cancer; ERK; 1/2; KRAS; PI3K; PTEN; ONCOGENIC K-RAS; CYCLE ARREST; TUMOR PROGRESSION; POTENT INHIBITOR; KINASE CASCADE; ERK1/2; PATHWAY; PIK3CA GENE; IN-VIVO; B-RAF; MUTATIONS;
D O I
10.1002/ijc.24604
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Mutations in KRAS (or BRAF frequently manifest in constitutive activation of the MEK1/2-ERK1/2 signalling pathway. The MEK1/2-selective inhibitor, AZD6244 (ARRY-1.42886), blocks ER.K1/2activation and is currently undergoing clinical evaluation. Tumour cells can vary markedly in their response to MAPK or ERK kinase (MEK.) inhibitors, and the presence of a BRAF mutation is thought to predict sensitivity, with the RAS mutations being associated with intrinsic resistance. We analysed cell proliferation in a panel of 19 colorectal cancer cell lines and found no simple correlation between BRAF or KRAS mutation and sensitivity to AZD6244, though cells that harbour neither mutation tended to be resistant. Cells that were sensitive arrested in G., and/or underwent apoptosis and the presence of BRAF or KRAS mutation was not sufficient to predict either fate. Cell lines that were resistant to AZD6244 exhibited low or no ERK1/2 activation (or exhibited coincident activation of ERK1/2 and protein kinase B (PI(B), the latter indicative of activation of the PI3K pathway. In cell lines with coincident ERK1/2 and PKB activation. sensitivity to AZD6244 could be re-imposed by any of the 3 distinct PI3K/mTOR inhibitors. We conclude that AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with high ERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and lend to be sensitive to AZD6244 but this call he offset by high PI3K-dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors. (C) 2009 UICC
引用
收藏
页码:2332 / 2341
页数:10
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