Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA315450 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms. Total RNA was isolated 6h and 24h after treatment with 1 M-NM-<M NVP-BEZ235 or DMSO vehicle control from 3D grown structures
2012-03-13 | E-GEOD-28992 | biostudies-arrayexpress
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms.
2012-03-13 | GSE28992 | GEO
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound.
2013-12-14 | GSE53309 | GEO
Project description:Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL
| PRJNA231653 | ENA
Project description:We discover drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network Achieving robust cancer-specific lethality is the ultimate clinical goal. Here we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally up-regulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 up-regulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
2018-02-23 | GSE104301 | GEO
Project description:MYC drives resistance to PI3K/mTOR targeted inhibition (gene expression)
| PRJNA142801 | ENA
Project description:MYC drives resistance to PI3K/mTOR targeted inhibition (Sty SNP array)
| PRJNA142799 | ENA
Project description:Copy number profiling of 92 human lung tumors on Affymetrix 100K SNP arrays was conducted in order to assess the interaction of common genomic alterations with response to targeted anti-cancer therapeutics. Class 1 phosphatidylinositol 3' kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here we investigate biomarker strategies for PI3K pathway inhibitors in non-small-cell lung cancer (NSCLC). Molecular profiling of NSCLC tumor samples showed that copy number gains in PIK3CA and total loss of PTEN protein were common in squamous cell carcinoma samples, whereas LKB1 loss and mutations in KRAS and EGFR were common in adenocarcinomas. A panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers. Cell lines harboring pathway alterations (RTK activation, PI3K mutation or amplification, PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a MEK inhibitor had greater effects on cell viability than PI3K inhibition alone. CONCLUSIONS: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with non-squamous NSCLC patient populations. Lung tumors were profiled on Affymetrix GeneChip Mapping 100K Set Arrays Tumor samples were profiled for copy number without any treatment of the tumor.
2013-01-10 | E-GEOD-39793 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE25170: MYC drives resistance to PI3K/mTOR targeted inhibition (Sty SNP array) GSE25172: MYC drives resistance to PI3K/mTOR targeted inhibition (gene expression) Refer to individual Series
2011-09-13 | E-GEOD-25173 | biostudies-arrayexpress