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Inhibition of Transforming Growth Factor Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness

Scios Inc., Fremont, California

Transforming growth factor (TGF) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF receptor I kinase (TGFRI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF-dependent Smad2 phosphorylation and expression of TGF-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGFRI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.

Address correspondence to: Dr. Nicholas J. Gaspar, 6500 Paseo Padre Parkway, Fremont, CA 94555. E-mail: gaspar.nj{at}gmail.com

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