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HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models

2014; Impact Journals LLC; Volume: 5; Issue: 16 Linguagem: Inglês

10.18632/oncotarget.2231

1949-2553

Gaëlle Thomas, Thierry Chardès, Nadège Gaborit, Caroline Mollévi, Wilhem Leconet, Bruno Robert, Nina Radosevic‐Robin, Frédérique Penault‐Llorca, Céline Gongora, Pierre‐Emmanuel Colombo, Yassamine Lazrek, Rui Bras-Gonçalves, Ariel Savina, D. Azria, Hervé Bazin, André Pèlegrin, Christel Larbouret,

Cell Adhesion Molecules Research

// Gaëlle Thomas 1,2 , Thierry Chardès 1 , Nadège Gaborit 1 , Caroline Mollevi 5 , Wilhem Leconet 1 , Bruno Robert 1 , Nina Radosevic-Robin 3 , Frédérique Penault-Llorca 3 , Céline Gongora 1 , Pierre-Emmanuel Colombo 1 , Yassamine Lazrek 1,4 , Rui Bras-Goncalves 1 , Ariel Savina 6 , David Azria 1 , Hervé Bazin 7 , André Pèlegrin 1 and Christel Larbouret 1 1 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 2 Institut Roche de Recherche et Médecine Translationnelle, Boulogne Bilancourt, France 3 Department of Biopathology, The Jean Perrin Comprehensive Cancer Center and ERTICa Research Group, University of Auvergne EA4677, Clermont-Ferrand, France 4 Millegen SA, F-31681, Labège, France 5 Unité de Biostatistiques, ICM Val d'Aurelle, Montpellier, France 6 Roche SAS Scientific Partnerships, Boulogne Billancourt, France 7 CisBio Bioassays, Le Codolet, France Correspondence: Christel Larbouret, email: // Keywords : HER3; HER2; pertuzumab; pancreatic cancer Received : June 30, 2014 Accepted : July 16, 2014 Published : July 17, 2014 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 HER2 low -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 HER2 low -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.