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

Index: Nat. Commun. 6 , 6175, (2015)

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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.