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RELIEF OF PROFOUND FEEDBACK INHIBITION OF MITOGENIC SIGNALING BY RAF INHIBITORS ATTENUATES THEIR ACTIVITY IN BRAFV600E MELANOMAS

Lito, Piro and Pratilas, Christine and Joseph, Eric and Tadi, Madhavi and Halilovic, Ensar and Zubrowski, Matt and Huang, Alan and Wong, Wai Lin and Callahan, Margaret and Merghoub, Taha and Wolchok, Jedd and DeStanchina, Elisa and Chandarlapaty, Sarat and Poulikakos, Poulikos and Fagin, James and Rosen, Neal (2012) RELIEF OF PROFOUND FEEDBACK INHIBITION OF MITOGENIC SIGNALING BY RAF INHIBITORS ATTENUATES THEIR ACTIVITY IN BRAFV600E MELANOMAS. Cancer Cell, 22 (5). pp. 668-682. ISSN 1535-6108

Abstract

BRAFV600E drives tumors by dysregulating ERK signaling. Here we show that, in these
tumors, high levels of ERK-dependent negative feedback potently suppress liganddependent
mitogenic signaling and Ras function. BRAFV600E activation is Rasindependent
and 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 ERKpathway
inhibition and antitumor activity.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7773

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