title: Examination of HER3 targeting in cancer using monoclonal antibodies.
abstract: The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.
authors.affiliation: Departments of Biological Regulation.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gaborit
authors.affiliation: Departments of Biological Regulation, Department of Internal Medicine, Kaplan Medical Center, Rehovot 76100, Israel.
authors.forename: Ali
authors.initials: A
authors.lastname: Abdul-Hai
authors.affiliation: Departments of Biological Regulation.
authors.forename: Maicol
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Departments of Biological Regulation.
authors.forename: Moshit
authors.initials: M
authors.lastname: Lindzen
authors.affiliation: Departments of Biological Regulation.
authors.forename: Sara
authors.initials: S
authors.lastname: Lavi
authors.affiliation: Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Orith
authors.initials: O
authors.lastname: Leitner
authors.affiliation: Cisbio Bioassays, Innovation Management, Parc Marcel Boiteux, 30200 Codolet, France; and.
authors.forename: Lucile
authors.initials: L
authors.lastname: Mounier
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier, France;
authors.forename: Myriam
authors.initials: M
authors.lastname: Chentouf
authors.affiliation: Departments of Biological Regulation.
authors.forename: Sai
authors.initials: S
authors.lastname: Dunoyer
authors.affiliation: Departments of Biological Regulation.
authors.forename: Manjusha
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier, France;
authors.forename: Christel
authors.initials: C
authors.lastname: Larbouret
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
authors.affiliation: Cisbio Bioassays, Innovation Management, Parc Marcel Boiteux, 30200 Codolet, France; and.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bazin
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier, France;
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.affiliation: Immunology, and yosef.yarden@weizmann.ac.il michael.sela@weizmann.ac.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Sela
authors.affiliation: Departments of Biological Regulation, yosef.yarden@weizmann.ac.il michael.sela@weizmann.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D020893:Receptor, ErbB-3 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: HER3; antibody combination; cancer therapy; signal transduction; tyrosine kinase