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)
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: | 16 Jul 2021 19:54 |
| PMCID: | PMC4049532 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/29959 |
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