ADAM8 as a drug target in pancreatic cancer

Uwe Schlomann; Garrit Koller; Catharina Conrad; Taheera Ferdous; Panagiota Golfi; Adolfo Molejon Garcia; Sabrina Höfling; Maddy Parsons; Patricia Costa; Robin Soper; Maud Bossard; Thorsten Hagemann; Rozita Roshani; Norbert Sewald; Randal R Ketchem; Marcia L Moss; Fred H Rasmussen; Miles A Miller; Douglas A Lauffenburger; David A Tuveson; Christopher Nimsky; Jörg W Bartsch

doi:10.1038/ncomms7175

ADAM8 as a drug target in pancreatic cancer

Nat Commun. 2015 Jan 28:6:6175. doi: 10.1038/ncomms7175.

Authors

Uwe Schlomann¹, Garrit Koller², Catharina Conrad³, Taheera Ferdous², Panagiota Golfi², Adolfo Molejon Garcia², Sabrina Höfling², Maddy Parsons⁴, Patricia Costa⁵, Robin Soper⁵, Maud Bossard⁵, Thorsten Hagemann⁵, Rozita Roshani⁵, Norbert Sewald⁶, Randal R Ketchem⁷, Marcia L Moss⁸, Fred H Rasmussen⁸, Miles A Miller⁹, Douglas A Lauffenburger⁹, David A Tuveson¹⁰, Christopher Nimsky³, Jörg W Bartsch¹

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / antagonists & inhibitors
ADAM Proteins / metabolism*
Animals
Blotting, Western
Carcinoma, Pancreatic Ductal / enzymology
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Cell Movement / drug effects
Extracellular Space / metabolism
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Gene Knockdown Techniques
Humans
Hydroxamic Acids / pharmacology
Hydroxamic Acids / therapeutic use
Integrin beta1 / metabolism
Kaplan-Meier Estimate
Matrix Metalloproteinase 14 / metabolism
Matrix Metalloproteinase 2 / metabolism
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / metabolism*
Mice
Molecular Targeted Therapy*
Neoplasm Invasiveness
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / enzymology
Pancreatic Neoplasms / pathology
Peptides, Cyclic / pharmacology
Peptides, Cyclic / therapeutic use
Phosphorylation / drug effects
Protein Binding / drug effects
Protein Multimerization / drug effects
Protein Processing, Post-Translational
Signal Transduction / drug effects

Substances

Hydroxamic Acids
Integrin beta1
Membrane Proteins
Peptides, Cyclic
Focal Adhesion Protein-Tyrosine Kinases
ADAM Proteins
ADAM8 protein, human
Matrix Metalloproteinase 2
Matrix Metalloproteinase 14

Abstract

Publication types

MeSH terms

Substances

Grants and funding