ADAM8 as a drug target in pancreatic cancer
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ADAM8 as a drug.pdf
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Author(s)
Schlomann, Uwe
Koller, Garrit
Conrad, Catharina
Ferdous, Taheera
Golfi, Panagiota
Garcia, Adolfo Molejon
Höfling, Sabrina
Parsons, Maddy
Costa, Patricia
Soper, Robin
Date Issued
January 2015
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Schlomann, Uwe et al. “ADAM8 as a Drug Target in Pancreatic Cancer.” Nature Communications 6 (2015): 6175.
Version
Author's final manuscript
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[superscript G12D]-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/ncomms7175
