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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis
  • Cancer-Associated Fibroblasts / drug effects*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / prevention & control*
  • Cell Proliferation
  • Coculture Techniques
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neuregulin-1 / antagonists & inhibitors*
  • Neuregulin-1 / immunology
  • Neuregulin-1 / metabolism
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / prevention & control*
  • Receptor, ErbB-3 / antagonists & inhibitors*
  • Receptor, ErbB-3 / immunology
  • Receptor, ErbB-3 / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • NRG1 protein, human
  • Neuregulin-1
  • ERBB3 protein, human
  • Receptor, ErbB-3