title: HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models.
abstract: The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France. Institut Roche de Recherche et Médecine Translationnelle, Boulogne Bilancourt, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Thomas
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gaborit
authors.affiliation: Unité de Biostatistiques, ICM Val d'Aurelle, Montpellier, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mollevi
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Wilhem
authors.initials: W
authors.lastname: Leconet
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
authors.affiliation: Department of Biopathology, The Jean Perrin Comprehensive Cancer Center and ERTICa Research Group, University of Auvergne EA4677, Clermont-Ferrand, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.affiliation: Department of Biopathology, The Jean Perrin Comprehensive Cancer Center and ERTICa Research Group, University of Auvergne EA4677, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gongora
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Colombo
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France. Millegen SA, F-31681, Labège, France.
authors.forename: Yassamine
authors.initials: Y
authors.lastname: Lazrek
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Rui
authors.initials: R
authors.lastname: Bras-Goncalves
authors.affiliation: Roche SAS Scientific Partnerships, Boulogne Billancourt, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Azria
authors.affiliation: CisBio Bioassays, Le Codolet, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bazin
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, 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, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Larbouret
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D011897:Random Allocation; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C485206:pertuzumab