Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors

Lito, P., Saborowski, A., Yue, J., Solomon, M., Joseph, E., Gadal, S., Saborowski, M., Kastenhuber, E., Fellmann, C., Ohara, K., Morikami, K., Miura, T., Lukacs, C., Ishii, N., Lowe, S., Rosen, N. (April 2014) Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors. Cancer Cell, 25 (5). pp. 697-710. ISSN 1878-3686 (Electronic)1535-6108 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24746704
DOI: 10.1016/j.ccr.2014.03.011

Abstract

MEK inhibitors are clinically active in BRAFV600E melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAFV600E, than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAFV600E. MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

Item Type: Paper
Additional Information: Meeting abstract
Subjects: diseases & disorders > cancer
Publication Type > Meeting Abstract
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 15 April 2014
Date Deposited: 02 May 2014 13:49
Last Modified: 06 Feb 2018 16:55
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29959

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