Abstract Activation of ERK signaling causes feedback inhibition of receptor tyrosine kinase and RAS signaling by multiple mechanisms and limits the steady-state output of the pathway. The V600E BRAF mutant does not depend on RAS-dependent dimerization and is not susceptible to feedback inhibition of RAS. In V600E BRAF melanomas, ERK pathway output and the expression of ERK genes such as DUSP6 and members of the SPROUTY family are markedly elevated. In these tumors, RTK signaling and RAS activation are actively suppressed. In the context of elevated DUSP6, RAF inhibitors rapidly inhibit ERK phosphorylation and output. This relieves the feedback inhibition of various RTKs and induces RAS activity and the formation of activated wild type RAF dimers that are insensitive to RAF-inhibitors. This results in a rebound in ERK phosphorylation and output that is sensitive to MEK, but not RAF inhibitors and suggests that the latter cannot maximally inhibit ERK signaling in these tumors. In support of this idea, combined treatment with MEK and RAF inhibitors reduces ERK output and the growth of V600E BRAF melanoma xenografts to a greater degree than either alone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1223. doi:1538-7445.AM2012-1223