Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC.

• Authors: Daniel Massó-Vallés, Toni Jauset, Erika Serrano, Nicole M Sodir, Kim Pedersen, Nesrine I Affara, Jonathan R Whitfield, Marie-Eve Beaulieu, Gerard I Evan, Laurence Elias, Joaquín Arribas, Laura Soucek
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 8 Pg. 1675-81 (Apr 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25878147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Female
• Fibrosis (prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, pathology)
• Piperidines
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Tumor Cells, Cultured
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays