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

Research output: Contribution to journalArticlepeer-review

Abstract

BRAFV600E 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. BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)668-682
Number of pages15
JournalCancer cell
Volume22
Issue number5
DOIs
StatePublished - Nov 13 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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