Disruption of CRAF-Mediated MEK activation is required for effective mek inhibition in KRAS mutant tumors Journal Article


Authors: 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.
Article Title: Disruption of CRAF-Mediated MEK activation is required for effective mek inhibition in KRAS mutant tumors
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 mutanttumors. 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. © 2014 Elsevier Inc.
Journal Title: Cancer Cell
Volume: 25
Issue: 5
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2014-05-12
Start Page: 697
End Page: 710
Language: English
DOI: 10.1016/j.ccr.2014.03.011
PROVIDER: scopus
PUBMED: 24746704
PMCID: PMC4049532
DOI/URL:
Notes: Cancer Cell -- Export Date: 2 June 2014 -- CODEN: CCAEC -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    383 Rosen
  2. Piro Lito
    22 Lito
  3. Scott W Lowe
    174 Lowe
  4. Eric William Joseph
    13 Joseph
  5. Jingyin Yue
    2 Yue
  6. Sunyana   Gadal
    2 Gadal