Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma through derepression of DUSP1 phosphatase and inhibition of ERK

ABSTRACT: We have investigated the role of the Notch pathway in the generation and maintenance of KrasG12V-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and Rbpj activities are both essential in the formation of NSCLCs. Interestingly, pharmacologic treatment of mice carrying endogenous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth and induces partial regression. Treated cancers show a reduction in Hes1 levels, reduced phosphorylated Erk, decreased proliferation and higher apoptosis. We demonstrate that HES1 directly binds and represses the promoter of DUSP1, a dual phosphatase with activity against phospho-ERK, and this repression is relieved by GSI treatment both in mouse and human NSCLCs. Our data provide proof for the in vivo therapeutic potential of γ-secretase inhibitors in primary NSCLCs and provide a mechanistic explanation for its therapeutical effect. We have included 6 samples. 3 with vehicle and 3 with the gamma-secretase inhibitor DAPT and we compare both groups.

ORGANISM(S): Homo sapiens

SUBMITTER: Antonio Maraver

PROVIDER: E-GEOD-38054 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK.

Maraver Antonio A Fernández-Marcos Pablo J PJ Herranz Daniel D Muñoz-Martin Maribel M Gomez-Lopez Gonzalo G Cañamero Marta M Mulero Francisca F Megías Diego D Sanchez-Carbayo Marta M Shen Jie J Sanchez-Cespedes Montserrat M Palomero Teresa T Ferrando Adolfo A Serrano Manuel M

Cancer cell 20120801 2

Here, we have investigated the role of the Notch pathway in the generation and maintenance of Kras(G12V)-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and RBPJ are essential for the formation of NSCLCs. Of importance, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and reduced phosphorylated ERK without changes in phosphorylated ...[more]

PMID: 22897852

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Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.

Dataset Information

Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma through derepression of DUSP1 phosphatase and inhibition of ERK

Publications

Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK.

Similar Datasets

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