title: Inhibition of TGF-β Signaling in Tumor Cells by Small Molecule Src Family Kinase Inhibitors.
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.
authors.affiliation: First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bartscht
authors.affiliation: First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rosien
authors.affiliation: Department of Radiation Oncology, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rades
authors.affiliation: Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena. Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Biersack
authors.affiliation: First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnerta
authors.affiliation: First Department of Medicine, UKSH, Campus Lubeck, D-23538 Lubeck. Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ungefroren
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta; D019061:src-Family Kinases
keywords: Src; TGF-beta; epithelial-mesenchymal transition; kinase inhibitor; migration; pancreatic cancer