MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors

Alexa B. Turke, Youngchul Song, Carlotta Costa, Rebecca Cook, Carlos L. Arteaga, John M. Asara, Jeffrey A. Engelman

Research output: Contribution to journalArticlepeer-review

271 Scopus citations


The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found thatMEKinhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer.

Original languageEnglish (US)
Pages (from-to)3228-3237
Number of pages10
JournalCancer research
Issue number13
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors'. Together they form a unique fingerprint.

Cite this