title: Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors.
abstract: Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor.
authors.affiliation: INSERM U563, Université Paul Sabatier, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Zindy
authors.forename: Yann
authors.initials: Y
authors.lastname: Bergé
authors.forename: Ben
authors.initials: B
authors.lastname: Allal
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierredon
authors.forename: Anne
authors.initials: A
authors.lastname: Cammas
authors.forename: Samantha
authors.initials: S
authors.lastname: Beck
authors.forename: Loubna
authors.initials: L
authors.lastname: Mhamdi
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.forename: Stéphan
authors.initials: S
authors.lastname: Vagner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D005260:Female; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000068818:Cetuximab; D066246:ErbB Receptors; D039562:Eukaryotic Initiation Factor-4F; D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C087000:EIF4EBP1 protein, human; C508053:ERBB2 protein, human