A Specific Inhibitor of TGF-B Receptor Kinase, SB-431542, as a Potent Antitumor Agent for Human Cancers1

Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-B (TGF-B) in advanced stage carcinogenesis pro-vides a potentially interesting drug target for thera-peutic intervention. Although very few TGF-B receptor kinase inhibitors (TRKI) are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-B, or when these inhibitors might be useful for treatment during cancer progres-sion. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-B– induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-B, including TGF-B–induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-B, whereas it reduces colony formation by cells that are growth-promoted by TGF-B. However, SB-431542 has no effect on a cell line that failed to respond to TGF-B. This represents a novel potential application of these inhi-bitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-B– induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-B