ADAM8 as a drug target in Pancreatic Cancer

Uwe Schlomann, Garrit Koller, Catharina Conrad, Taheera Ferdous, Panagiota Golfi, Adolfo Molejon Garcia, Sabrina Hofling, Madeline 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. TuvesonChristopher Nimsky, Joerg Bartsch

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)


Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. In PDAC cell lines, ADAM8 expression is associated with increased migration and invasiveness caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation 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 multimerisation. In PDAC cell lines, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 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 KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.
Original languageEnglish
Article number6175
Number of pages15
JournalNature Communications
Issue number1
Early online date28 Jan 2015
Publication statusPublished - 28 Jan 2015


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