Author/Authors :
Lito، نويسنده , , Piro and Pratilas، نويسنده , , Christine A. and Joseph، نويسنده , , Eric W. and Tadi، نويسنده , , Madhavi and Halilovic، نويسنده , , Ensar and Zubrowski، نويسنده , , Matthew and Huang، نويسنده , , Alan and Wong، نويسنده , , Wai Lin and Callahan، نويسنده , , Margaret K. and Merghoub، نويسنده , , Taha and Wolchok، نويسنده , , Jedd D. and de Stanchina، نويسنده , , Elisa and Chandarlapaty، نويسنده , , Sarat and Poulikakos، نويسنده , , Poulikos I. and Fagin، نويسنده , , James A. and Rosen، نويسنده , , Neal، نويسنده ,
Abstract :
Summary
00E 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.
