Title:Inhibition of TGF-β Signaling in Tumor Cells by Small Molecule Src Family Kinase Inhibitors
Volume: 17
Issue: 10
Author(s): Tobias Bartscht, Benjamin Rosien, Dirk Rades, Roland Kaufmann, Harald Biersack, Hendrik Lehnerta and Hendrik Ungefroren*
Affiliation:
- First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck,Germany
Keywords:
TGF-beta, Src, kinase inhibitor, pancreatic cancer, migration, epithelial-mesenchymal transition.
Abstract: In a series of studies carried out over the last couple of years in various cell types, it was observed that
the experimentally used Src family kinase inhibitors PP1 and PP2 and the clinically used Src/Abl inhibitors
AZM475271 and dasatinib are potent inhibitors of TGF-β mediated cellular responses such as Smad and p38
mitogen-activated protein kinase phosphorylation, Smad-dependent transcriptional activation, growth inhibition,
epithelial-mesenchymal transition (EMT), and cell motility. While for PP1/PP2 it was demonstrated that these
agents directly inhibit the kinase activity of the TGF-β type I receptor activin receptor-like kinase 5, the
mechanism of the anti-TGF-β effect of AZM475271 and dasatinib is less clear. In contrast, the anti-TGF-β effect
of yet another Src/Abl inhibitor, bosutinib, is more variable with respect to the type of the TGF-β response and
the cell type affected, and lacks a clear dose-dependency. In the light of their strong anti-activin receptor-like
kinase 5 kinase effect, PP1 and PP2 should not be used when studying the role of c-Src as downstream mediators
in TGF-β/activin receptor-like kinase 5 signaling. On the other hand, based upon in vitro findings, it is
conceivable that part of the therapeutic effects of AZM475271 and dasatinib seen in preclinical and clinical
studies with solid tumors was caused by inhibition of prometastatic TGF-β rather than Src signaling. If
AZM475271 and dasatinib can indeed act as dual Src / TGF-β inhibitors in vivo, this may be beneficial for
prevention of metastatic disease in more advanced tumor stages.
