ADAM8 as a drug target in pancreatic cancer

  • Nat Commun. 2015 Jan 28;6:6175. doi: 10.1038/ncomms7175.
Uwe Schlomann  1 ,  Garrit Koller  2 ,  Catharina Conrad  3 ,  Taheera Ferdous  2 ,  Panagiota Golfi  2 ,  Adolfo Molejon Garcia  2 ,  Sabrina Höfling  2 ,  Maddy Parsons  4 ,  Patricia Costa  5 ,  Robin Soper  5 ,  Maud Bossard  5 ,  Thorsten Hagemann  5 ,  Rozita Roshani  5 ,  Norbert Sewald  6 ,  Randal R Ketchem  7 ,  Marcia L Moss  8 ,  Fred H Rasmussen  8 ,  Miles A Miller  9 ,  Douglas A Lauffenburger  9 ,  David A Tuveson  10 ,  Christopher Nimsky  3 ,  Jörg W Bartsch  1
Affiliations
  • 1. 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.
  • 2. King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
  • 3. Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
  • 4. King's College London, Randall Institute, London SE1 8RT, UK.
  • 5. Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
  • 6. Department of Organic Chemistry, Bielefeld University, 33615 Bielefeld, Germany.
  • 7. Therapeutic Discovery, AMGEN Inc., Seattle, Washington 98119, USA.
  • 8. Biozyme Inc., Apex, North Carolina 27523, USA.
  • 9. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  • 10. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11791, USA.
PMID: 25629724 DOI: 10.1038/ncomms7175
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.

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