Abstract: |
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. © 2012 Elsevier Inc. |
Keywords: |
signal transduction; epidermal growth factor; mitogen activated protein kinase; controlled study; unclassified drug; raf protein; nonhuman; protein function; mouse; melanoma; steady state; map kinase signaling system; protein kinase inhibitor; animal experiment; animal model; mitogenesis; enzyme activity; cell line, tumor; gene expression regulation, neoplastic; sulfonamides; intracellular signaling peptides and proteins; ligand; extracellular signal-regulated map kinases; ligands; ras protein; ras proteins; negative feedback; indoles; b raf kinase; fibroblast growth factors; monomer; proto-oncogene proteins b-raf; neratinib; receptors, growth factor; dimer; raf protein inhibitor; vemurafenib; attenuation; hepatocyte growth factor; dabrafenib; trametinib; b raf v600e protein; n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide; neuregulins
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