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Updated: Jan 30, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain
Matthew L Hemming1,2, Matthew A Lawlor3, Jessica L Andersen2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. mhemming@partners.org.
Abstract:
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist. In this study, we identify regulatory regions of the KIT enhancer essential for KIT gene expression and GIST cell viability. Given the dependence of GIST upon enhancer-driven expression of RTKs, we hypothesized that the enhancer domains 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 superior cytotoxic effects in vitro and in vivo, with BBI preventing tumor growth in TKI-resistant xenografts. Resistance to select BBI in GIST was attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST. SIGNIFICANCE: Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
Insights
BET bromodomain inhibitors target the KIT enhancer in gastrointestinal stromal tumors (GIST), reducing oncogene expression and halting cancer growth. This offers a new therapeutic strategy for GIST, even in cases resistant to kinase inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Gastrointestinal stromal tumors (GIST) are driven by activating mutations in KIT or PDGFRA receptor tyrosine kinases (RTKs).
- GIST cells depend on high RTK expression, regulated by a large enhancer domain, for tumor growth.
- Current therapies like kinase inhibitors are effective but often face resistance, necessitating novel treatment strategies.
Purpose of the Study:
- To identify essential regulatory regions of the KIT enhancer crucial for GIST cell viability.
- To investigate the therapeutic potential of BET bromodomain inhibitors (BBIs) in targeting GIST by modulating enhancer activity.
- To evaluate the efficacy of combining BBIs with tyrosine kinase inhibitors (TKIs) for GIST treatment.
Main Methods:
- Identification of critical regulatory regions within the KIT enhancer.
- Treatment of GIST cells with BBIs to assess effects on cell viability, cell-cycle arrest, and apoptosis.
- Genome-wide analysis of enhancer landscape (H3K27ac) and gene expression changes upon BBI treatment.
- In vitro and in vivo evaluation of combination therapy with BBIs and TKIs.
- Investigation of mechanisms of BBI resistance, including drug efflux pumps.
Main Results:
- BBIs induce cell-cycle arrest, apoptosis, and cell death in GIST cells by attenuating the KIT enhancer and reducing KIT gene expression.
- BBI treatment alters the genome-wide H3K27ac enhancer landscape and gene expression in KIT-dependent GIST cells.
- Combination therapy with BBIs and TKIs demonstrates superior cytotoxic effects in vitro and in vivo.
- BBIs effectively prevent tumor growth in TKI-resistant GIST xenografts.
- Drug efflux pumps are identified as a mechanism of resistance to certain BBIs in GIST.
Conclusions:
- The KIT enhancer represents a therapeutic vulnerability in GIST, targetable by BET bromodomain inhibitors.
- BBIs offer a novel therapeutic strategy for GIST, particularly in cases resistant to conventional kinase inhibitors.
- Combination therapy with BBIs and TKIs shows significant promise for overcoming GIST resistance and improving treatment outcomes.
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