AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only ackn...

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Published in:	Molecular cancer therapeutics Vol. 6; no. 8; pp. 2209 - 2219
Main Authors:	Davies, Barry R, Logie, Armelle, McKay, Jennifer S, Martin, Paul, Steele, Samantha, Jenkins, Richard, Cockerill, Mark, Cartlidge, Sue, Smith, Paul D
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research 01-08-2007
Subjects:	Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Benzimidazoles - administration & dosage Benzimidazoles - pharmacokinetics Benzimidazoles - pharmacology Cancer therapy Cell Death - drug effects Cell Line, Tumor Cell Survival - drug effects Dose-Response Relationship, Drug Drug Evaluation, Preclinical Drug Therapy, Combination Female Humans MEK inhibitor Mice Mice, Nude Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors preclinical Xenograft Model Antitumor Assays
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Summary:	Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel. [Mol Cancer Ther 2007;6(8):2209–19]
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.MCT-07-0231