Resistance to MEK Inhibitors: Should We Co-Target Upstream?

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Science Signaling  29 Mar 2011:
Vol. 4, Issue 166, pp. pe16
DOI: 10.1126/scisignal.2001948


  • Fig. 1

    Amplification of the oncogenic driver of ERK pathway activity confers resistance to MEK inhibitors. The RAF-MEK-ERK pathway is a three-tiered kinase cascade with a central role in regulating cell proliferation and survival. In cells with wild-type BRAF, RAS proteins activate the RAF kinases [ARAF, BRAF, and CRAF (RAF1)] in part by facilitating their dimerization. Activated RAF phosphorylates MEK1 and MEK2 (MEK), which in turn phosphorylate ERK1 and ERK2 (ERK). ERK pathway activation in BRAF(V600E) mutant cells is RAS-independent and does not require the formation of RAF dimers. The ERK pathway contains a classical feedback loop in which the abundance of feedback elements, such as Sprouty and dual-specificity phosphatase family proteins, is determined by ERK activity.


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