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Cancer Cell. 2014 May 12;25(5):697-710. doi: 10.1016/j.ccr.2014.03.011. Epub 2014 Apr 17.

Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.

Author information

1
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
5
Research Division, Chugai Pharmaceutical, Kamakura, 247-8530, Japan.
6
Roche Research Center, Hoffmann-La Roche, Nutley, NJ 07110, USA.
7
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
8
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rosenn@mskcc.org.

Abstract

MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), 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 BRAF(V600E). 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.

PMID:
24746704
PMCID:
PMC4049532
DOI:
10.1016/j.ccr.2014.03.011
[Indexed for MEDLINE]
Free PMC Article

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