Gene expression data from rapamycin resistant and sensitive cell lines
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE19885 | GEO | 2013/02/08
SECONDARY ACCESSION(S): PRJNA123699
REPOSITORIES: GEO
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Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation. Inhibitors of mTOR are being evaluated as anti-tumor agents. Given the emerging role of microRNAs (miRNAs) in tumorgenesis we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Rapamycin resistant myogenic cells developed by long-term rapamycin treatment showed extensive reprogramming of miRNAs expression, characterized by up-regulation of the mir-17~92 and related clusters and down-regulation of tumor-suppressor miRNAs. Antagonists of oncogenic miRNA families and mimics of tumor suppressor miRNAs (let-7) restored rapamycin sensitivity in resistant tumor cells. This study identified miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors.
2013-02-08 | GSE19916 | GEO
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation. Inhibitors of mTOR are being evaluated as anti-tumor agents. Given the emerging role of microRNAs (miRNAs) in tumorgenesis we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Rapamycin resistant myogenic cells developed by long-term rapamycin treatment showed extensive reprogramming of miRNAs expression, characterized by up-regulation of the mir-17~92 and related clusters and down-regulation of tumor-suppressor miRNAs. Antagonists of oncogenic miRNA families and mimics of tumor suppressor miRNAs (let-7) restored rapamycin sensitivity in resistant tumor cells. This study identified miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors. Total RNA extraction and hybridization on Affymetrix microarrays of rapamycin sensitive (RS) cells (BC3H1, mouse brain tumor cell line with myogenic properties, ATCC) cultured in Dulbecco’s modified essential medium (DMEM) media supplemented with 20% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100 mg/ml). Rapamycin resistant cells (RR1) were developed by culturing BC3H1 cells in the presence of 1 uM rapamycin for 6 months. Three samples in triplicates: 1) Rapamycin sensitive cells treated with DMSO for 24 h(BC3H1, reference), 2) Rapamycin sensitive cells treated for 24 h with 100 nM rapamycin (BC3H1+R), 3) Rapamycin resistant cells constantly treated with 1uM Rapamycion (RR1+R).
2013-02-08 | E-GEOD-19885 | biostudies-arrayexpress
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation. Inhibitors of mTOR are being evaluated as anti-tumor agents. Given the emerging role of microRNAs (miRNAs) in tumorgenesis we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Rapamycin resistant myogenic cells developed by long-term rapamycin treatment showed extensive reprogramming of miRNAs expression, characterized by up-regulation of the mir-17~92 and related clusters and down-regulation of tumor-suppressor miRNAs. Antagonists of oncogenic miRNA families and mimics of tumor suppressor miRNAs (let-7) restored rapamycin sensitivity in resistant tumor cells. This study identified miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors. Total RNA was extracted from rapamycin sensitive (RS) cells (BC3H1, mouse brain tumor cell line with myogenic properties, ATCC) cultured in Dulbecco’s modified essential medium (DMEM) media supplemented with 20% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100 mg/ml). Rapamycin resistant cells (RR1) were developed by culturing BC3H1 cells in the presence of 1 uM rapamycin for 6 months. Three samples in quadruplicate 1)RS cells treated with DMSO for 24 h(BC3H1, reference), 2) RS cells treated for 24 h with 100 nM rapamycin (BC3H1+R), 3) RR1 cells consantly treated with 1uM Rapamycion (RR1+R). For each experiment, 1 μM of total RNA was labeled with Hy3TM dye and a reference RNA pool (consisting of a mixture of equal amounts of total RNA from BC3H1, BC3H1+R and RR1+R cells) was labeled with Hy5TM dye using the miRCURYTM Labeling Kit. The samples were hybridized to Exiqon miRCURYTM LNA Arrays (V10.0).
2013-02-08 | E-GEOD-19916 | biostudies-arrayexpress
Project description:Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Keywords: Comparative Genomic Hybridization
2008-01-29 | GSE7344 | GEO
Project description:To determine differential metabolic gene expression in distinct cell populations from subcutaneous MC38 tumors at baseline and in response to rapamycin, tumors from mice treated with vehicle or rapamycin were harvested, reconstituted to single cell suspensions, and flow sorted into cancer cell (CD45-), tumor-associated macrophage (TAM, CD45+ CD11b+ Ly6G- Ly6C lo F4/80 hi), monocytic myeloid-derived suppressor cell (M-MDSC, CD45+ CD11b+ Ly6G- Ly6C hi), CD8 T cell (CD45+ CD3+ CD8a+), and CD4 T cell (CD45+ CD3+ CD8a-) populations. RNA was extracted and transcripts were quantified by the NanoString nCounter Metabolic Pathways Panel.
2021-02-26 | GSE165223 | GEO
Project description:This study investigates the safety/toxicity and potential anti-tumor activity of sequential administration of nivolumab and escalating doses of the mTOR inhibitor ABI-009 in advanced Ewing’s sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors
| 2247222 | ecrin-mdr-crc
Project description:p73 is a p53 family transcription factor that plays critical roles during development and tumor suppression. We analyzed p73 activity using a combination of ChIP-on-Chip and gene expression profiling, both at baseline and after treatment with the mTOR inhibitor rapamycin. We report the first comprehensive analysis of p73 binding across the genome. Furthermore, we re-analyzed this p73 cistrome after perturbation with rapamycin, an inhibitor of mTOR and inducer of p73. Multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR.
2011-01-05 | GSE15704 | GEO
Project description:Phosphoinositide-3-kinase (PI3K)-α inhibitors are clinically active in squamous carcinoma (SCC) of the head and neck (H&N) bearing mutations or amplification of PIK3CA. We aimed to identify potential mechanism of resistance and have observed that SCCs cells overcome the antitumor effects of the PI3Kα inhibitor BYL719 by maintaining PI3K-independent activation of the mammalian target of rapamycin (mTOR). The persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. We found that AXL is overexpressed in resistant tumors, dimerizes with the epidermal growth factor receptor (EGFR), phosphorylates EGFR tyrosine 1173, resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC) that, in turn, activates mTOR. Finally, simultaneous treatment with PI3Kα and either EGFR, AXL or PKC inhibitors reverts this resistance. RNAseq from acquired resistant cells CAL33B, K180B were compared to their parental counterpart CAL33 and K180, respectively. K180 is a shortcut of KYSE180, and B stands for BYL719. Duplicate of parental sensitive cells and K180B, and triplicate for CAL33B.
2015-04-12 | E-GEOD-61515 | biostudies-arrayexpress
Project description:We hypothesize that, the mTOR pathway is a dominant pathway in cultured keloid and hypertrophy scar fibriblasts compared to normal skin cells. Certain pathway changes can be detected after medication treatment. Global gene expression in RNA samples from rapamycin and tacrolimus treated fibroblasts (from normal skin and hypertrophic scars, keloid scars) is assayed to study the possibility to use mTOR inhibitors as potential drug to treat abnormal scarring. We investigated the difference between normal wound healing and hypertrophic scars and keloids as well.
2014-05-20 | E-MTAB-2509 | biostudies-arrayexpress
Project description:Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process of effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Results: Colony formation and sulforhodamine B (IC50 < 1nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI was significantly associated with tumor size or lymph node status. High (>75) percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.01) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In Wang dataset, RMI predicted time to disease relapse (P = 0.09). Conclusions: Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment. Mol Cancer. 2009 Sep 24;8(1):75. Experiment Overall Design: Rapamycin treatment of MDA-MB-468 breast cancer cell line: Experiment Overall Design: MDA-MB-468 cell line was treated by DMSO (vehicle) and 100 nM rapamycin for 24 hours. We sought to identify differentially expressed genes. Experiment Overall Design: Rapamycin treatment of breast tumor xenografts: Experiment Overall Design: MDA-MB-468 cells were inoculated in the mammary fat pad of female nude mice. When resulting tumor volumes had reached 75-150 mm3, the mice were divided in four groups. Groups 1 and 2 received a single injection of DMSO (vehicle) or rapamycin (15 mg/kg) intraperitoneally and sacrificied 24 h later (1-day groups). Groups 3 and 4 received weekly injections of DMSO or rapamycin for 3 weeks and sacrificied 24 h after the last injection (22-day groups).
2009-12-02 | E-GEOD-18571 | biostudies-arrayexpress