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

Piro Lito; Christine A Pratilas; Eric W Joseph; Madhavi Tadi; Ensar Halilovic; Matthew Zubrowski; Alan Huang; Wai Lin Wong; Margaret K Callahan; Taha Merghoub; Jedd D Wolchok; Elisa de Stanchina; Sarat Chandarlapaty; Poulikos I Poulikakos; James A Fagin; Neal Rosen

doi:10.1016/j.ccr.2012.10.009

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

Cancer Cell. 2012 Nov 13;22(5):668-82. doi: 10.1016/j.ccr.2012.10.009.

Authors

Piro Lito¹, Christine A Pratilas, Eric W Joseph, Madhavi Tadi, Ensar Halilovic, Matthew Zubrowski, Alan Huang, Wai Lin Wong, Margaret K Callahan, Taha Merghoub, Jedd D Wolchok, Elisa de Stanchina, Sarat Chandarlapaty, Poulikos I Poulikakos, James A Fagin, Neal Rosen

Affiliation

¹ Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Epidermal Growth Factor / metabolism
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Extracellular Signal-Regulated MAP Kinases / physiology
Fibroblast Growth Factors / metabolism
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor / metabolism
Humans
Indoles / pharmacology
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Intracellular Signaling Peptides and Proteins / physiology
Ligands
MAP Kinase Signaling System / drug effects*
Melanoma / genetics*
Melanoma / metabolism
Membrane Proteins
Neuregulins / metabolism
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins B-raf / metabolism
Proto-Oncogene Proteins B-raf / physiology
Receptors, Growth Factor / metabolism
Sulfonamides / pharmacology
Vemurafenib
ras Proteins / antagonists & inhibitors*
ras Proteins / metabolism
ras Proteins / physiology

Substances

HGF protein, human
Indoles
Intracellular Signaling Peptides and Proteins
Ligands
Membrane Proteins
Neuregulins
Receptors, Growth Factor
SPRY2 protein, human
Sulfonamides
Vemurafenib
Fibroblast Growth Factors
Epidermal Growth Factor
Hepatocyte Growth Factor
BRAF protein, human
Proto-Oncogene Proteins B-raf
Extracellular Signal-Regulated MAP Kinases
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding