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|Ref Type||Journal Article|
|Authors||Nam AR, Kim JW, Park JE, Bang JH, Jin MH, Lee KH, Kim TY, Han SW, Im SA, Kim TY, Oh DY, Bang YJ|
|Title||Src as a Therapeutic Target in Biliary Tract Cancer.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515-24. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|SRC positive||biliary tract cancer||sensitive||Bosutinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Bosulif (bosutinib) inhibited Src signaling, resulted in cell cycle arrest and decreased invasion of biliary tract cancer cell lines in culture, and delayed tumor growth in cell line xenograft models (PMID: 27196758).||27196758|
|SRC positive||biliary tract cancer||sensitive||Bosutinib + Gemcitabine||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Bosulif (bosutinib) and Gemzar (gemcitabine) synergistically inhibited Src signaling, decreased proliferation and migration of billary tract cancer cell lines in culture, and inhibited tumor growth in cell line xenograft models (PMID: 27196758).||27196758|
|SRC positive||biliary tract cancer||sensitive||Bosutinib + Cisplatin||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Bosulif (bosutinib) and Platinol (cisplatin) synergistically inhibited Src signaling, decreased proliferation and migration of billary tract cancer cell lines in culture, and inhibited tumor growth in cell line xenograft models (PMID: 27196758).||27196758|