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Published on: January 12, 2020
Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors
Amaury G Dumont1, Yanwen Yang, David Reynoso
1Department of Sarcoma Medical Oncology, University of Texas-MD Anderson Cancer Center Houston, TX, USA.
Abstract:
Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may lead the development of new therapeutic strategies for GISTs patients.
Insights
The Notch pathway acts as a tumor suppressor in gastrointestinal stromal tumors (GISTs), inhibiting KIT oncogene activity. Activating this pathway offers a potential new therapy for GIST patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- Gastrointestinal stromal tumors (GISTs) are driven by KIT/PDGFRA mutations, with imatinib resistance being a significant clinical challenge.
- The Notch signaling pathway is a conserved developmental pathway implicated in various cancers, with roles as either a tumor promoter or suppressor.
- Interstitial cells of Cajal, the progenitor cells for GISTs, share neuroendocrine-like characteristics, suggesting a potential role for Notch signaling in GIST biology.
Purpose of the Study:
- To investigate the impact of the Notch pathway on GIST cell biology.
- To explore the therapeutic potential of modulating the Notch pathway in GIST.
- To evaluate Hes1, a Notch target gene, as a prognostic marker in GIST patients.
Main Methods:
- Retroviral and pharmacological manipulation of the Notch pathway in human GIST cells.
- In vitro assessment of Notch1 intracellular domain (ICN1) expression on GIST cell growth and KIT expression.
- Treatment of GIST cells with histone deacetylase (HDAC) inhibitors and Notch pathway inhibitors (γ-secretase inhibitors).
- Retrospective analysis of Hes1 mRNA levels in 15 primary GIST tumors.
Main Results:
- Constitutively active Notch1 (ICN1) expression induced GIST cell growth arrest and downregulated KIT expression.
- Histone deacetylase inhibitor treatment upregulated Notch1 and decreased GIST cell viability.
- Inhibition of Notch signaling partially rescued GIST cells from HDAC inhibitor effects.
- High Hes1 mRNA levels in GIST patients correlated with significantly longer relapse-free survival.
Conclusions:
- The Notch pathway exhibits anti-tumor effects in GISTs, potentially through negative feedback with the KIT oncogene.
- Activation of the Notch pathway, particularly with HDAC inhibitors, represents a promising therapeutic strategy for GIST.
- Hes1 serves as a valuable prognostic biomarker for predicting relapse-free survival in GIST patients.
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