Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Cavalloni, Giuliana; Peraldo-Neia, Caterina; Sarotto, Ivana; Gammaitoni, Loretta; Migliardi, Giorgia; Soster, Marco; Marchiò, Serena; Aglietta, Massimo; Leone, Francesco

doi:10.1158/1535-7163.mct-11-1020

Cited by 13 publications

(10 citation statements)

References 39 publications

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“…Figure 4a–d shows that the wound in MT-CHC01 cells was significantly closed at 24, 48, and 72 h after the wound; the migration potential of MT-CHC01 is lower if compared to other commercial cell lines such as HuH28 (Fig. 4e), that closes the wound within 24 h as previously demonstrated [ 38 ]. This data was confirmed by transwell chamber assay (Fig.…”

Section: Resultssupporting

confidence: 71%

Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient

et al. 2015

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Biliary tract carcinoma is a rare malignancy with multiple causes, which underlie the different genetic and molecular profiles. Cancer cell lines are affordable models, reflecting the characteristics of the tumor of origin. They represent useful tools to identify molecular targets for treatment. Here, we established and characterized from biological, molecular, and genetic point of view, an Italian intrahepatic cholangiocarcinoma cell line (ICC), the MT-CHC01. MT-CHC01 cells were isolated from a tumor-derived xenograft. Immunophenotypical characterization was evaluated both at early and after stabilization passages. In vitro biological, genetic, and molecular features were also investigated. In vivo tumorigenicity was assessed in NOD/SCID mice. MT-CHC01cells retain epithelial cell markers, EPCAM, CK7, and CK19, and some stemness and pluripotency markers, i.e., SOX2, Nanog, CD49f/integrin-α6, CD24, PDX1, FOXA2, and CD133. They grow as a monolayer, with a population double time of about 40 h; they show a low migration and invasion potential. In low attachment conditions, they are able to form spheres and to growth in anchorage-independent manner. After subcutaneous injection, they retain in vivo tumorigenicity; the expression of biliary markers as CA19-9 and CEA were maintained from primary tumor. The karyotype is highly complex, with a hypotriploid to hypertriploid modal number (3n+/−) (52 to 77 chromosomes); low level of HER2 gene amplification, TP53 deletion, gain of AURKA were identified; K-RAS G12D mutation were maintained from primary tumor to MT-CHC01 cells. We established the first ICC cell line derived from an Italian patient. It will help to study either the biology of this tumor or to test drugs both in vitro and in vivo.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-015-4215-3) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 71%

Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient

et al. 2015

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“…A previous study indicated that about 80% of BTC specimens expressed an activated Src protein similar to other malignancies (3)(4)(5)(6)18). In our study, a total of nine BTC cell lines were tested, and the IC 50 values ranged from 0.63 to 4.45 mmol/L in 3-day MTT assays.…”

Section: Discussionmentioning

confidence: 83%

“…A recent study demonstrated that Src is also frequently overexpressed in BTC as in other malignant diseases, although its relationship with clinicopathologic parameters or histologic origin was not significant (18). In addition, blocking Src activity by novel Src inhibitors such as saracatinib (AZD-0530) and AZM555130 reduced the proliferative and invasive potential of human BTC cell lines (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, blocking Src activity by novel Src inhibitors such as saracatinib (AZD-0530) and AZM555130 reduced the proliferative and invasive potential of human BTC cell lines (18,19). However, these studies used only a limited number of BTC cell lines and only tested Src inhibitor monotherapy, without investigating combination strategies with other chemotherapeutic agents that are already approved for BTC treatment.…”

Section: Introductionmentioning

confidence: 99%

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Src as a Therapeutic Target in Biliary Tract Cancer

Nam

Kim

Park

et al. 2016

Molecular Cancer Therapeutics

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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 G 1 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. Ó2016 AACR.

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“…Several Src kinase inhibitors such as bosutinib, dasatinib, and ponatinib have been developed and approved as anticancer drugs by the United States Food and Drug Administration. However, the therapeutic efficacies of Src inhibitors as single agents in treating various solid tumors are not encouraging, due to the intrinsic complexity of Src signaling and the redundant pathways involved in tumor development [41][42][43][44][45]. Therefore, the development of diagnostic markers is urgently needed for the preselection of potential responders to anti-Src therapy to enhance clinical benefits.…”

Section: Discussionmentioning

confidence: 99%

Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

et al. 2020

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Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

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Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Cited by 13 publications

References 39 publications

Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient

Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient

Src as a Therapeutic Target in Biliary Tract Cancer

Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

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