RRC ID 43755
Author Cavalloni G, Peraldo-Neia C, Sarotto I, Gammaitoni L, Migliardi G, Soster M, Marchiò S, Aglietta M, Leone F.
Title Antitumor activity of Src inhibitor saracatinib (AZD-0530) in preclinical models of biliary tract carcinomas.
Journal Mol. Cancer Ther.
Abstract Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G(0)-G(1) phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 μmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib-based clinical applications.
Volume 11(7)
Pages 1528-38
Published 2012-7
DOI 10.1158/1535-7163.MCT-11-1020
PII 1535-7163.MCT-11-1020
PMID 22452946
MeSH Aged Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Benzodioxoles / administration & dosage Benzodioxoles / pharmacology* Biliary Tract Neoplasms / drug therapy Biliary Tract Neoplasms / genetics Biliary Tract Neoplasms / metabolism* Carcinoma / drug therapy Carcinoma / genetics Carcinoma / metabolism* Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Enzyme Activation / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Humans Male Mice Mice, Inbred NOD Mice, SCID Middle Aged Neovascularization, Pathologic / drug therapy Phosphorylation Quinazolines / administration & dosage Quinazolines / pharmacology* Tumor Burden / drug effects Xenograft Model Antitumor Assays src-Family Kinases / antagonists & inhibitors*
IF 5.365
Times Cited 5
WOS Category ONCOLOGY
Resource
Human and Animal Cells