title: 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.
authors.affiliation: Gastrointestinal Medical Oncology Program, University of Colorado Cancer Center, 12801 East 17th Avenue, Aurora, CO 80045, USA. Wells.Messersmith@ucdenver.edu
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Xiao Fei
authors.initials: XF
authors.lastname: Wang
authors.forename: Veronica
authors.initials: V
authors.lastname: Diesl
authors.forename: Sung E
authors.initials: SE
authors.lastname: Choe
authors.forename: Max
authors.initials: M
authors.lastname: Follettie
authors.forename: Christina
authors.initials: C
authors.lastname: Coughlin
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Garcia
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopez-Rios
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000493:pharmacokinetics / Q000494:pharmacology*; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D051242:Caveolin 1; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib; D015688:Oncogene Protein pp60(v-src)