Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts.
Recently， tyrosine kinase has emerged as an attractive target for anticancer therapy， and is overexpressed in . The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of (SKI-606)， a /inhibitor， using a panel of xenografts. Surgically resected were implanted into female and randomized to versus control. and other pathways were analyzed by Western Blot， IHC， and Affymetrix U133 2.0 gene arrays. Of 15 patient ， 3 patient were found to be sensitive to ， defined as of <45% than that of control . There were no definite differences between sensitive and resistant in the baseline kinase pathway expression assessed by Western Blot. expression， as assessed by -PCR and immunohistochemistry， was frequently higher in sensitive cases. In sensitive ， resulted in increased apoptosis. of key molecules downstream of ， ， and ， were significantly inhibited by . 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 and other inhibitors in .