title: The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation.
abstract: We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Clorennec
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.|Millegen SA, Labège, F-31670, France.|Institut Pasteur de Guyane, BP 6010, 97306, Cayenne Cedex, France.
authors.forename: Yassamine
authors.initials: Y
authors.lastname: Lazrek
authors.affiliation: Millegen SA, Labège, F-31670, France.|GamaMabs Pharma SA, Centre Pierre Potier, ONCOPOLE, BP 50624, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubreuil
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Larbouret
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
authors.forename: Marie-Alix
authors.initials: MA
authors.lastname: Poul
authors.affiliation: Millegen SA, Labège, F-31670, France.|LFB Biotechnologies, 59000, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mondon
authors.affiliation: Biochemistry Laboratory, Instituto Dermopatico Dell'Immacolata, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata," 00133 Rome, Italy.|Toxicology Unit, Medical Research Council, Leicester University, Leicester LE1 9HN, United Kingdom.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194 Montpellier, Montpellier, F-34298, France.|Université de Montpellier, Montpellier, F-34298, France.|ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000625864:9F7-F11 antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D012097:Repressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D048056:Mitogen-Activated Protein Kinase 9; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D048055:Mitogen-Activated Protein Kinase 8
keywords: HER3; ITCH/AIP4; antibody; cancer; treatment