title: Antitumor activity of Src inhibitor saracatinib (AZD-0530) in preclinical models of biliary tract carcinomas.
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.
authors.affiliation: Department of Medical Oncology, University of Turin Medical School, Turin, Italy. giuliana.cavalloni@ircc.it
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cavalloni
authors.forename: Caterina
authors.initials: C
authors.lastname: Peraldo-Neia
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Loretta
authors.initials: L
authors.lastname: Gammaitoni
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Marco
authors.initials: M
authors.lastname: Soster
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Francesco
authors.initials: F
authors.lastname: Leone
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases