Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

Abstract

Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer.

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

“…Inhibition of MAPK T202/204 phosphorylation by SKI-606, which is most likely more indirect, has been reported by others to be transient in MDA-MB-468 cells (19). Modest inhibition of AKT phosphorylation on Ser 473 by SKI-606 in MB-MDA-231 cells was reported by us (18) but is not always observed (19,27). Interestingly, recent studies using biopsy samples from patients with breast cancer link Src activity to AKT activation and bone metastasis (28).…”

Current Status of Src Inhibitors in Solid Tumor Malignancies

“…Src inhibitors inhibit the growth of human pancreas tumor explants in preclinical models [45,46]. Activated Src also increases levels of IGF-1R with a subsequent increase in IGF-dependent cell proliferation [47].…”

Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies

“…In vitro, inhibitors of Src inhibit growth and migration in a variety of neoplastic solid tumor cell lines, including breast, prostate, colon, pancreatic, and lung (17,(22)(23)(24)(25)(26)(27). Use of Src inhibitors leads to decreased phosphorylation of multiple Src substrates including mitogen-activated protein kinase (MAPK), FAK, Akt, and subsequent growth inhibition (24,28).…”