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Differentially expressed genes and chromosomal alterations in ovarian cancer cell lines sensitive or resistant to a Src-inihibitor, saracatinib

ABSTRACT: We sought to detect predictive markers related to a Src kinase inhibitor (saracatinib) sensitivity in ovarian cancer. Cell proliferation assays assigned 18 ovarian cancer cell lines to sensitive or resistant to this drug. Using baseline gene expression data from these 18 cell lines, we sought to identify differentially expressed genes correlated with saracatinib sensitivity. We also used SNP array data from 7 cell lines to detect differentically affected genomic locations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55628 | GEO | 2017/03/05

SECONDARY ACCESSION(S): PRJNA240296

REPOSITORIES: GEO

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EGI-1 cell line treated with Saracatinib vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib vs EGI-1 untreated

Project description:Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is therefore urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the non-receptor 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 BTC patients. 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 G0/G1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26 to 6.99 µM), Saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, Saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. We here 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. EGI-1 cell line treated with Saracatinib at the dose of 10 µM vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib at the dose of 25 mg/Kg/die vs EGI-1 xenograft untreated Transcriptional alteration mediated by Saracatinib in vitro and in vivo

2012-08-02 | E-GEOD-36622 | biostudies-arrayexpress

Oxaliplatin resistance is enhanced by saracatinib via upregulation of ABCG1 and Wnt/β-catenin signaling in hepatocellular carcinoma

Project description:Background:Oxaliplatin-resistant hepatocellular carcinoma (HCC) is associated with increased insulin-like growth factor 1 (IGF1) paracrine signaling, and the IGF1 receptor can be downregulated by inhibition of Src kinases. Therefore, we sought to determine whether Src inhibition and oxaliplatin treatment exerted synergistic effects on HCC cell lines. Methods: The antitumor effects of combined treatment with saracatinib and oxaliplatin on proliferation were evaluated in HCC cells as well as in saracatinib- and oxaliplatin-resistant HCC cell lines using cell viability assays, plate colony formation assays, and cell cycle distribution detection. RNA sequencing was used to explore the resistance mechanism, and the effects on ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. Furthermore, treatment with saracatinib caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in the HCC cell lines. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the upregulation of ABCG1 and activation of Wnt signaling pathway by saracatinib.

2019-03-30 | GSE129071 | GEO

EGI-1 cell line treated with Saracatinib vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib vs EGI-1 untreated

2012-08-03 | GSE36622 | GEO

Dual inhibition of Src and MEK decreases the growth of human ovarian cancer cells

Project description:Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors, saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell cycle arrest in vitro and tumor inhibition in xenografts.

2018-03-28 | GSE112371 | GEO

Saracatinib Promotes Definitive Endoderm Differentiation by Inhibition of FAK-YAP Signaling Axis

Project description:Optimizing the efficiency of definitive endoderm differentiation is significant for the generation of diverse organ-like structures. In this study, we utilized saracatinib to enhance definitive endoderm differentiation in pluripotent stem cells. We found saracatinib significantly improved the definitive endoderm differentiation at low concentrations. To investigate the impact of 0.5 μM saracatinib on definitive endoderm differentiation of ESC H1 cells, we conducted RNA-seq analysis with differentiated cells with or without 0.5 μM saracatinib treatment.

2023-12-24 | GSE251992 | GEO

Common PIK3CA mutants and a novel 3’UTR mutation are associated with increased sensitivity to saracatinib

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IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

Project description:We identified IGF2BP1 as a marker of the C5 molecular subtype of high-grade ovarian carcinoma (HG-SOC). IGF2BP1 promotes SRC activity and ERK2 expression enhancing the tolerance towards SRC- and MEK-directed inhibitors saracatinib and selumetib. Combination treatment overcomes IGF2BP1-promoted resistance.

2020-08-24 | GSE147980 | GEO

Saracatinib drug treatment of mouse primary microglia cultures

Project description:To test the effect of saracatinib on gene expression patterns in microglia, we treated mouse (C57BL/6) primary microglial cultures with saracatinib (1microM, 24h) versus DMSO vehicle control and quantified gene expression. Sequencing libraries were prepared using the Lexogen QuantSeq 3'Forward kit with sequencing performed on an Illumina HiSeq 4000 (single end reads 1 x 65; 5M reads per sample). For processed data, reads were aligned against GRCm38 and quantified using STAR. Samples were normalized with CQN. Batch correction was completed using ComBat from sva version 3.6.0.

2020-11-05 | GSE146865 | GEO

Saracatinib inhibits TGF-β–induced phenotypic changes in human lung fibroblasts

Project description:Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications.We investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in in vitro modele using normal human lung fibroblasts (NHLFs).

2022-08-30 | GSE178518 | GEO

Common PIK3CA mutants and a novel 3’UTR mutation are associated with increased sensitivity to saracatinib

Project description:Sensitive versus Resistant patient-derived colorectal cancer tumor xenografts with PIK3CA mutant against saracatinib (AZD0530)

2012-02-24 | GSE36006 | GEO

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