Journal
CANCER CELL
Volume 22, Issue 5, Pages 668-682Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.10.009
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Funding
- National Institutes of Health [P01-CA129243, K08-CA127350]
- Melanoma Research Alliance
- STARR Cancer Consortium
- Experimental Therapeutics Center of MSKCC
- Harry J. Lloyd Charitable Trust
- Charles A. Dana Foundation
- Commonwealth Foundation for Cancer Research
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BRAF(V600E) drives tumors by dysregulating ERK signaling. In these tumors, we show that high levels of ERK-dependent negative feedback potently suppress ligand-dependent mitogenic signaling and Ras function. BRAF(V600E) activation is Ras independent and it signals as a RAF-inhibitor-sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP, and generation of RAF-inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK pathway inhibition and antitumor activity.
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