title: 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: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Daniel
authors: D
authors: Massó-Vallés
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Toni
authors: T
authors: Jauset
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Erika
authors: E
authors: Serrano
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Nicole M
authors: NM
authors: Sodir
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Kim
authors: K
authors: Pedersen
authors: Department of Pathology, University of California, San Francisco, California.
authors: Nesrine I
authors: NI
authors: Affara
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Jonathan R
authors: JR
authors: Whitfield
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Marie-Eve
authors: ME
authors: Beaulieu
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. Department of Pathology, University of California, San Francisco, California.
authors: Gerard I
authors: GI
authors: Evan
authors: Pharmacyclics Inc., Sunnyvale, California.
authors: Laurence
authors: L
authors: Elias
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors: Joaquín
authors: J
authors: Arribas
authors: Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. lsoucek@vhio.net.
authors: Laura
authors: L
authors: Soucek
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005355:Fibrosis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine