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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Piro
authors.initials: P
authors.lastname: Lito
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.forename: Eric W
authors.initials: EW
authors.lastname: Joseph
authors.forename: Madhavi
authors.initials: M
authors.lastname: Tadi
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.forename: Matthew
authors.initials: M
authors.lastname: Zubrowski
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.forename: Wai Lin
authors.initials: WL
authors.lastname: Wong
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Poulikos I
authors.initials: PI
authors.lastname: Poulikakos
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D020880:Neuregulins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017978:Receptors, Growth Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
chemical_list: C066855:HGF protein, human; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D020880:Neuregulins; D017978:Receptors, Growth Factor; C485561:SPRY2 protein, human; D013449:Sulfonamides; D000077484:Vemurafenib; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins