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Gene Expression Profiling of OPM2 treatment with VS-5584 (SB2343).

ABSTRACT: The PI3K/mTOR pathway is a constitutively active in multiple myeloma. Single inhibition of mTOR usually confers reactivation of the pathway. VS-5584 (SB2343) is a bispecific PI3K/mTOR inhibitor which effectively and specifically inhibits the target pathways and shows potent anti-myeloma activity. We utilised a gene microarray analysis to analyse and identify the genes that were sensitively regulated by VS-5584 treatment in OPM2. OPM2 cells were either treated with DMSO(drug solvent) or with 125nM of VS-5584(SB2343) which is half the IC50 concentration of the drug at 48h in OPM2 cells. The cells were harvested at 24h in order to detect the regulation of relatively early response genes.

ORGANISM(S): Homo sapiens

SUBMITTER: Nurulhuda Mustafa

PROVIDER: E-GEOD-84862 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene Expression Profiling of OPM2 treatment with VS-5584 (SB2343).

Project description:The PI3K/mTOR pathway is a constitutively active in multiple myeloma. Single inhibition of mTOR usually confers reactivation of the pathway. VS-5584 (SB2343) is a bispecific PI3K/mTOR inhibitor which effectively and specifically inhibits the target pathways and shows potent anti-myeloma activity. We utilised a gene microarray analysis to analyse and identify the genes that were sensitively regulated by VS-5584 treatment in OPM2.

2016-07-27 | GSE84862 | GEO

Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL

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

Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL

2013-12-14 | GSE53309 | GEO

Resistance to PI3K/mTOR inhibitor PF-04691502 in KRAS mutant colorectal cancer models reveals a sensitivity to combination with EGFR inhibition

Project description:We explored potential bypass mechanisms to PI3K/mTOR-directed therapy in KRAS mutant CRC models, utilizing genetically engineered mouse models (GEMM) to generate acquired resistance to the targeted dual PI3K/mTOR small molecule inhibitor PF-04691502. Transcriptomic analysis revealed a dynamic stem-like progenitor signature which was increased in the presence of drug pressure.

2014-08-31 | E-MTAB-2510 | biostudies-arrayexpress

Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture

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

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Drug resistance-related changes in gene expression profile in multiple myeloma

Project description:1) We identified the genes whose expression was up- and down-regulated by the adhesion to bone marrow stromal cells in human multiple myeloma cell line RPMI8226. 2) We identified the genes whose expression was up- and down-regulated by the PI3K inhibitor PF-04691502 in human multiple myeloma cell line RPMI8226. We isolated mRNA from the multiple myeloma cell line RPMI8226 under drug-resistant conditions, and subjected them to gene expression profiling using an Agilent GeneChip Array.

2015-03-04 | E-GEOD-66466 | biostudies-arrayexpress

Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture

2012-03-13 | GSE28992 | GEO

PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis

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

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors

Project description:This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.

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RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition

Project description:Fang L, Ford-Roshon D, Russo M, O'Brien C, Xiong X, Gurjao C, Grandclaudon M, Raghavan S, Corsello SM, Carr SA, Udeshi ND, Berstler J, Sicinska E, Ng K, Giannakis M. 2022. The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

2022-04-29 | MSV000089343 | MassIVE

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