title: ADAM8 as a drug target in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with <5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK1/2 and higher MMP activities. For biological function, ADAM8 requires multimerization and associates with β1 integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a Kras(G12D)-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.
authors: 1] King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK [2] Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
authors: Uwe
authors: U
authors: Schlomann
authors: King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
authors: Garrit
authors: G
authors: Koller
authors: Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
authors: Catharina
authors: C
authors: Conrad
authors: King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
authors: Taheera
authors: T
authors: Ferdous
authors: King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
authors: Panagiota
authors: P
authors: Golfi
authors: King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
authors: Adolfo Molejon
authors: AM
authors: Garcia
authors: King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
authors: Sabrina
authors: S
authors: Höfling
authors: King's College London, Randall Institute, London SE1 8RT, UK.
authors: Maddy
authors: M
authors: Parsons
authors: Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Patricia
authors: P
authors: Costa
authors: Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Robin
authors: R
authors: Soper
authors: Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Maud
authors: M
authors: Bossard
authors: Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Thorsten
authors: T
authors: Hagemann
authors: Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Rozita
authors: R
authors: Roshani
authors: Department of Organic Chemistry, Bielefeld University, 33615 Bielefeld, Germany.
authors: Norbert
authors: N
authors: Sewald
authors: Therapeutic Discovery, AMGEN Inc., Seattle, Washington 98119, USA.
authors: Randal R
authors: RR
authors: Ketchem
authors: Biozyme Inc., Apex, North Carolina 27523, USA.
authors: Marcia L
authors: ML
authors: Moss
authors: Biozyme Inc., Apex, North Carolina 27523, USA.
authors: Fred H
authors: FH
authors: Rasmussen
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Miles A
authors: MA
authors: Miller
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Douglas A
authors: DA
authors: Lauffenburger
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11791, USA.
authors: David A
authors: DA
authors: Tuveson
authors: Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
authors: Christopher
authors: C
authors: Nimsky
authors: 1] King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK [2] Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
authors: Jörg W
authors: JW
authors: Bartsch
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D019012:Integrin beta1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; D019012:Integrin beta1; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051722:ADAM Proteins; C068490:ADAM8 protein, human; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14
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