ADAM8 as a drug target in pancreatic cancer
- Schlomann, U.
- Koller, G.
- Conrad, C.
- Ferdous, T.
- Golfi, P.
- Garcia, A. M.
- Hofling, S.
- Parsons, M.
- Costa, P.
- Soper, R.
- Bossard, M.
- Hagemann, T.
- Roshani, R.
- Sewald, N.
- Ketchem, R. R.
- Moss, M. L.
- Rasmussen, F. H.
- Miller, M. A.
- Lauffenburger, D. A.
- Tuveson, D. A.
- Nimsky, C.
- Bartsch, J. W.
DOIAbstract
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 beta1 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 ...
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