Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas Journal Article

Authors: Lito, P.; Pratilas, C. A.; Joseph, E. W.; Tadi, M.; Halilovic, E.; Zubrowski, M.; Huang, A.; Wong, W. L.; Callahan, M. K.; Merghoub, T.; Wolchok, J. D.; de Stanchina, E.; Chandarlapaty, S.; Poulikakos, P. I.; Fagin, J. A.; Rosen, N.
Article Title: Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas
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
Journal Title: Cancer Cell
Volume: 22
Issue: 5
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2012-11-13
Start Page: 668
End Page: 682
Language: English
DOI: 10.1016/j.ccr.2012.10.009
PROVIDER: scopus
PUBMED: 23153539
PMCID: PMC3713778
Notes: --- - "Export Date: 3 December 2012" - "CODEN: CCAEC" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. James A Fagin
    107 Fagin
  2. Neal Rosen
    356 Rosen
  3. Jedd D Wolchok
    637 Wolchok
  4. Taha Merghoub
    190 Merghoub
  5. Piro Lito
    15 Lito
  6. Margaret Kathleen Callahan
    100 Callahan
  7. Madhavi Tadi
    11 Tadi
  8. Eric William Joseph
    13 Joseph
  9. Wai Lin Wong
    4 Wong