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. (2015) ADAM8 as a drug target in pancreatic cancer. Nature Communications, 6. p. 6175. ISSN 2041-1723
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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 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 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab CSHL Cancer Center Program > Signal Transduction |
| Depositing User: | Matt Covey |
| Date: | 2015 |
| Date Deposited: | 06 Feb 2015 19:57 |
| Last Modified: | 16 Jul 2021 13:18 |
| PMCID: | PMC5014123 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/31185 |
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