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MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma (SCC)

ABSTRACT: Genomic analyses of SCC have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene expression between cisplatin-sensitive and -resistant SCC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66549 | GEO | 2015/08/05

SECONDARY ACCESSION(S): PRJNA277308

REPOSITORIES: GEO

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MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma (SCC)

Project description:Genomic analyses of SCC have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene expression between cisplatin-sensitive and -resistant SCC cells. Cisplatin-sensitive and -resistant SCC cells were identified through MTS assay. Gene expression profiling (Affymetrix GeneChip 1.0ST) was performed to identify putative genes and cellular pathways that may be associated with cellular response to cisplatin.

2015-08-05 | E-GEOD-66549 | biostudies-arrayexpress

Gene expression data from human NSCLC U1810 residual clones 9 days after a one-hour pulse treatment with cisplatin

Project description:Background: The platinum compounds cisplatin and carboplatin are the mainstay of chemotherapy for lung cancer; however, treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. Methods: We analyzed global gene expression profiles in NSCLC clones surviving a pulse treatment with cisplatin by microarray and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Results: Cisplatin-surviving NSCLC clones were demonstrated to have heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (DKK1), DNA repair machinery (XRCC2) and cell-cell/ cell-matrix interaction (FMN1 and LGALS9) were among the top deregulated genes by microarray and were subsequently validated by q-RT-PCR. We focused on DKK1, which was previously reported to be overexpressed in NSCLC. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones. Knockdown of DKK1 by siRNA sensitized untreated NSCLC cells to cisplatin, illustrating a putative role of DKK1 in intrinsic platinum resistance. Conclusions: Gene expression analysis identified DKK1 as a putative cisplatin resistance marker and a potential novel therapeutic target to overcome platinum resistance in NSCLC. U1810 cells were sparsely seeded for clonogenic survival assay in three separate experiments (replicate 1-3), left untreated or treated with cisplatin for 1 h and then kept for 9 days to assay long-term effects of a single pulse treatment.

2014-04-04 | E-GEOD-48244 | biostudies-arrayexpress

Gene expression data from human NSCLC U1810 residual clones 9 days after a one-hour pulse treatment with cisplatin

2014-04-04 | GSE48244 | GEO

CSL RNA-Seq on HKC and SCC cell lines

Project description:Down-modulation or loss-of-function mutations of the Notch 1 and 2 genes are associated with development of squamous cell carcinoma (SCC), a very frequent and therapy-resilient malignancy in skin, head/neck (H/N), lung and other surface epithelia. In this context, surprisingly little is known on the role of CSL (RBP-Jk), key effector of canonical Notch signaling endowed with intrinsic transcription repressive function. CSL expression is decreased in upper epidermal layers and differentiating primary human keratinocytes (HKCs), while it is up-regulated in premalignant and malignant SCC lesions and SCC cell lines from skin, Head/Neck and lung. Increased CSL levels enhance proliferation and self-renewal potential of HKCs and SCC cells, while its silencing induces growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels give rise to rapidly expanding tumors, while upon CSL silencing they form smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKC and SCC cells plus/minus CSL silencing reveals major modulation of apoptotic, cell cycle and pro-inflammatory genes, with no significant association with Notch or keratinocyte differentiation gene signatures. KDM6B, a histone demethylase gene with highly context dependent functions, is a direct CSL negative target, with an inverse role of CSL in HKC and SCC self-renewal and tumorigenesis, with IL6 as a target of likely significance. CSL / KDM6B protein expression could be used as biomarkers of SCC development and novel indicators of cancer treatment.

2017-12-15 | GSE102762 | GEO

MIcroRNA expression profiling of chemotherapy resistant esophageal adeno- and squamous cell carcinoma cell lines

Project description:Chemotherapy resistance adversely impacts the treatment of some individuals with esophageal cancer. Identifying chemotherapy resistance might help tailor clinical treatments. In this study the impact of microRNAs on chemotherapy resistance in esophageal cancer was investigated. We used microarrays to detail the global programme of microRNA expression underlying chemotherapy resistance and identified distinct classes of up-regulated microRNAs in generated chemotherapy resistant cell lines. An in-vitro model of acquired chemotherapy resistance in esophageal adeno- (EAC) and squamous cell carcinoma (SCC) cells was used, and microRNA expression profiles for cisplatin or 5-fluorouracil (FU) resistant variants vs. chemotherapy sensitive controls were compared using microarray. These results were further validated using qRT-PCR techniques (not shown in this submission).

2013-08-28 | E-GEOD-50224 | biostudies-arrayexpress

Genome-wide analysis of histone modification in UPCI-SCC-090, UM-SCC-104, FaDu and NP69SV40T.

Project description:We analysed active enhancers in UPCI-SCC-090, UM-SCC-104, FaDu and NP69SV40T by performing ChIP-seq on H3K4me3, H3K4me1 and H3K27ac.

2023-01-06 | GSE211473 | GEO

Identifying the downstream effectors of E2F7 in squamous cell carcinoma (SCC) cells

Project description:Advanced head and neck squamous cell carcinomas (HNSCC) are frequently drug resistant and have a mortality rate of 40%. We have previously shown that E2F7 may contribute to drug sensitivity. In the present study, we conducted an –omics screen to identify factors that were responsible for E2F7-dependent resistance to anthracyclines by HNSCC. We provide, in vitro, in vivo and patient data that identifies the existence of a novel E2F7/Sphingosine kinase 1/Sphingosine-1-phosphate/AKT axis that regulates sensitivity to anthracyclines in HNSCC. Specifically, we show that E2F7-dependent sensitivity to doxorubicin occurs via induction of the sphingosine kinase 1/AKT axis. We also show that pharmacological inhibition of Sphingosine kinase 1 or AKT sensitizes SCC cells to the cytotoxic actions of doxorubicin in vitro and in vivo. Combined, these findings highlight a novel mechanism through which SCC cells acquire resistance to anthracyclines and identify specific pharmacological combinations that could be used to treat SCC.

2014-05-30 | GSE58074 | GEO

Long noncoding RNAs expression patterns associated with chemo response to cisplatin based chemotherapy in lung squamous cell carcinoma patients

Project description:There is large variability among lung squamous cell carcinoma (SCC) patients in response to treatment with cisplatin based chemotherapy. LncRNAs is potentional a new type of predictive marker that can identify subgroups of patients who benefit from chemotherapy and it will have great value for treatment guidance. Differentially expressed LncRNAs were identified using microarray profiling of tumors with partial response (PR) vs. with progressive disease (PD) from advanced lung SCC patients treated with cisplatin based chemotherapy and validated by quantitative real-time PCR (qPCR). Results: Compared with the PD samples, 953 lncRNAs were consistently overregulated and 749 lncRNAs

2015-05-18 | E-GEOD-59245 | biostudies-arrayexpress

ST779-MRSA with a pseudo SCCmec-SCC-SCC (CRISPR)

Project description:WHole genome sequencing of a ST779-MRSA isolate identified a novel composite SCC element we have termed a pseudo SCCmec-SCC-SCC(CRISPR) element

| PRJEB224 | ENA

miRNA expression profiling in squamous cell carcinoma (SCC)

Project description:Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. We recently identified the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC, and demonstrated that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Reduced levels of GRHL3 and its target gene PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data defines the miR-21-GRHL3-PTEN-axis as a critical tumor suppressor pathway in SCC.

2013-01-18 | GSE32868 | GEO

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