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Cancer Lett. 2018 Sep 28;432:227-236. doi: 10.1016/j.canlet.2018.06.023. Epub 2018 Jun 20.

Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer.

Author information

1
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
2
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, F-34298, France; Institut régional du Cancer de Montpellier (ICM), Val d'Aurelle, Montpellier, F-34298, France.
3
Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
4
PhyMedExp, IPAM, University of Montpellier, INSERM U1046, CNRS UMR 9214, 34295, Montpellier cedex 5, France.
5
Institut régional du Cancer de Montpellier (ICM), Val d'Aurelle, Montpellier, F-34298, France.
6
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, F-34298, France. Electronic address: christel.larbouret@inserm.fr.

Abstract

Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC.

KEYWORDS:

Cancer-associated fibroblast; HER3; Immunotherapy; Neuregulin 1; Pancreatic cancer

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