title: MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.
abstract: 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 that MEK inhibitor-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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Turke
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cook
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D002460:Cell Line; D004789:Enzyme Activation; D005246:Feedback; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases