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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113217 | GEO | 2019/01/23

REPOSITORIES: GEO

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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition.

Project description: Not available

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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [RNA-seq]

Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.

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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [ChIP-seq]

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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition

Project description:Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition

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Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [RNA-seq]

Project description:Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [RNA-seq]

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Project description:Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [ChIP-seq]

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