Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668775 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12813830_1.fastq.gz | Fastqsanger.gz | |||
| SRR12813830_2.fastq.gz | Fastqsanger.gz | |||
| SRR12813831_1.fastq.gz | Fastqsanger.gz | |||
| SRR12813831_2.fastq.gz | Fastqsanger.gz | |||
| SRR12813832_1.fastq.gz | Fastqsanger.gz |
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Project description:Rigosertib treatment of head and neck squamous cell cancer The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in head and neck squamous cell cancer (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from 8 HNSCC patients (4 HPV16-positive). HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, western blotting, and IHC. Rigosertib had potent antiproliferative effects on 11 of the 16 HPV- HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in 3/8 HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA activating event (amplification or mutation) and a p53 inactivating event (either HPV16-mediated or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV+ and HPV- HNSCCs focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient for rigosertib-sensitivity. Sixteen HNSCC lines data were profiled at baseline to find differentially expressed genes and pathways sensitive to rigosertib.
2013-06-13 | E-GEOD-47864 | biostudies-arrayexpress
Project description:Rigosertib treatment of head and neck squamous cell cancer The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in head and neck squamous cell cancer (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from 8 HNSCC patients (4 HPV16-positive). HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, western blotting, and IHC. Rigosertib had potent antiproliferative effects on 11 of the 16 HPV- HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in 3/8 HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA activating event (amplification or mutation) and a p53 inactivating event (either HPV16-mediated or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV+ and HPV- HNSCCs focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient for rigosertib-sensitivity.
2013-06-13 | GSE47864 | 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. 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:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.
2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress
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
Project description:Blocking BRD4 or HDACs induces paradoxically similar gene expression, comparably attenuates PI3K/AKT inhibitor resistance in multiple cancer cells.
2020-09-09 | GSE137207 | GEO
Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC
2014-09-18 | GSE61495 | GEO
Project description:<p>These aggregate studies focus on specimens from head and neck squamous cell carcinoma (HNSCC) patients who were treated with standard of care or window of opportunity clinical trial approaches. Specimens were interrogated with exome and RNA-Seq analysis. Patient derived xenografts (PDXs) represent a robust platform for performing co-clinical trial approaches. In the first study we generated a large panel of PDXs and compared genomic profiles between the primary tumor and matched PDX with the patients blood serving as a source of somatic variants. In the second study, we performed a window of opportunity clinical trial in oral cavity squamous cell carcinoma patients using the MEK inhibitor trametinib. In addition, PDX models were generated from these specimens also and analyzed as in the first study. Finally, the third approach used pembrolizumab, an anti-PD1 blocking antibody, in a window of opportunity setting in HNSCC patients. For the latter two studies genomic matched sample analysis was performed to define response and resistance mechanisms. Together, these genomic data will inform several therapeutic approaches for HNSCC patients.</p>
| phs001623 | dbGaP
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress