title: Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation.
abstract: Blockade of the human epidermal growth factor receptor 3 (HER3) and of the downstream phosphatidylinositide 3-kinase (PI3K)/AKT pathway is a prerequisite for overcoming drug resistance and to develop novel treatments for cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2(low) cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G1 cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers.
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM Unit 896, Université Montpellier 1, CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
authors.forename: Yassamine
authors.initials: Y
authors.lastname: Lazrek
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubreuil
authors.forename: Véronique
authors.initials: V
authors.lastname: Garambois
authors.forename: Nadège
authors.initials: N
authors.lastname: Gaborit
authors.forename: Christel
authors.initials: C
authors.lastname: Larbouret
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Clorennec
authors.forename: Gaelle
authors.initials: G
authors.lastname: Thomas
authors.forename: Wilhem
authors.initials: W
authors.lastname: Leconet
authors.forename: Marta
authors.initials: M
authors.lastname: Jarlier
authors.forename: Martine
authors.initials: M
authors.lastname: Pugnière
authors.forename: Nadia
authors.initials: N
authors.lastname: Vié
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
authors.forename: Céline
authors.initials: C
authors.lastname: Monnet
authors.forename: Khalil
authors.initials: K
authors.lastname: Bouayadi
authors.forename: Hakim
authors.initials: H
authors.lastname: Kharrat
authors.forename: Philippe
authors.initials: P
authors.lastname: Mondon
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; D051636:X-Linked Inhibitor of Apoptosis Protein; C085126:FOXO1 protein, human