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

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.

Pubmed ID: 23153539

Authors

  • Lito P
  • Pratilas CA
  • Joseph EW
  • Tadi M
  • Halilovic E
  • Zubrowski M
  • Huang A
  • Wong WL
  • Callahan MK
  • Merghoub T
  • Wolchok JD
  • de Stanchina E
  • Chandarlapaty S
  • Poulikakos PI
  • Fagin JA
  • Rosen N

Journal

Cancer cell

Publication Data

November 13, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: K08 CA127350
  • Agency: NCI NIH HHS, Id: K08-CA127350
  • Agency: NCI NIH HHS, Id: P01 CA129243
  • Agency: NCI NIH HHS, Id: P01-CA129243
  • Agency: NCI NIH HHS, Id: P50 CA086438
  • Agency: NCI NIH HHS, Id: T32 CA062948

Mesh Terms

  • Cell Line, Tumor
  • Epidermal Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • Fibroblast Growth Factors
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Growth Factor
  • Humans
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • MAP Kinase Signaling System
  • Melanoma
  • Membrane Proteins
  • Neuregulins
  • Proto-Oncogene Proteins B-raf
  • Receptors, Growth Factor
  • Sulfonamides
  • ras Proteins