Research article summary (published 13 Nov 2009):

Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines.

Full Abstract

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-142886), blocks ERK1/2 activation 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(1) 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 (PKB), 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 tend to be sensitive to AZD6244 but this can be offset by high PI3K-dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors.

Author information

Author/s: Balmanno, Kathryn (K); Chell, Simon D (SD); Gillings, Annette S (AS); Hayat, Shaista (S); Cook, Simon J (SJ);

Affiliation: Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge, England, United Kingdom.

Grants: BB/C509190/1 (Agency:Biotechnology and Biological Sciences Research Council)

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Nov; vol 125 (issue 10) : pp 2332-41

Dates: Created 2009/09/28; Completed 2009/11/05;

PMID: 19637312, status: MEDLINE (last retrieval date: 11/5/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

1-Phosphatidylinositol 3-Kinase - metabolism Animals Apoptosis Benzimidazoles - pharmacology Blotting, Western Cell Line, Tumor Cell Proliferation Colorectal Neoplasms - drug therapy; metabolism; pathology Drug Resistance, Neoplasm Flow Cytometry Humans MAP Kinase Kinase 1 - antagonists & inhibitors; metabolism

MAP Kinase Kinase 1 - antagonists & inhibitors; metabolism MAP Kinase Kinase 2 - antagonists & inhibitors; metabolism Male Mice Mice, Inbred BALB C Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; metabolism Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; metabolism Mutation - genetics Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins B-raf - genetics RNA, Small Interfering - pharmacology ras Proteins - genetics

Associated Chemicals: AZD 6244 (0) ; Benzimidazoles (0) ; KRAS protein, human (0) ; Proto-Oncogene Proteins (0) ; RNA, Small Interfering (0) ; MAP Kinase Kinase 1 (EC 2.7.1.-) ; MAP Kinase Kinase 2 (EC 2.7.1.-) ; MAP2K1 protein, human (EC 2.7.1.-) ; MAP2K2 protein, human (EC 2.7.1.-) ; 1-Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; BRAF protein, human (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.1.37) ; Proto-Oncogene Proteins B-raf (EC 2.7.1.37) ; ras Proteins (EC 3.6.5.2)

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