| First Author | Schlomann U | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 6175 | PubMed ID | 25629724 |
| Mgi Jnum | J:219792 | Mgi Id | MGI:5629760 |
| Doi | 10.1038/ncomms7175 | Citation | Schlomann U, et al. (2015) ADAM8 as a drug target in pancreatic cancer. Nat Commun 6:6175 |
| abstractText | 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. |
