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Published on: May 2, 2022
The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors
James A DeCaprio1, Anette Duensing
1aDepartment of Medical Oncology, Dana-Farber Cancer Institute bDepartment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts cCancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center dDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Purpose Of Review:
Although most gastrointestinal stromal tumors respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), complete remissions are rare and the majority of patients achieve disease stabilization. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically.
Recent Findings:
Although imatinib induces apoptosis in a subset of gastrointestinal stromal tumor cells, it leads to a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex (DP, p130/RBL2, E2F4 and MuvB), a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A was shown to enhance imatinib-induced gastrointestinal stromal tumor cell death.
Summary:
Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses.
Insights
Gastrointestinal stromal tumors often survive imatinib treatment by entering a quiescent state regulated by the DREAM complex. Targeting this complex may improve therapeutic outcomes for patients with GIST.
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Gastrointestinal stromal tumors (GIST) typically respond to imatinib mesylate (Gleevec), but complete remission is rare.
- Residual GIST cells can persist under imatinib treatment, leading to eventual tumor progression upon treatment cessation.
- This persistence suggests a subpopulation of GIST cells remains viable despite imatinib therapy.
Purpose of the Study:
- To review the molecular mechanisms underlying GIST cell persistence during imatinib treatment.
- To explore therapeutic strategies targeting these persistent cells for improved treatment efficacy.
- To understand the role of cell cycle quiescence in GIST treatment resistance.
Main Methods:
- Review of existing literature on GIST, imatinib treatment, and cell cycle regulation.
- Analysis of the role of the DREAM complex in regulating quiescence in cancer cells.
- Discussion of potential therapeutic interventions targeting the DREAM complex and quiescence.
Main Results:
- Imatinib induces apoptosis in some GIST cells but causes others to enter a quiescent state (G0) via the DREAM complex.
- The DREAM complex (DP, p130/RBL2, E2F4, MuvB) is identified as a key regulator of this imatinib-induced quiescence.
- Inhibiting the DREAM complex, using siRNA or targeting its regulatory kinase (DYRK1A), enhances imatinib-induced GIST cell death.
Conclusions:
- Targeting the DREAM complex represents a promising therapeutic strategy to overcome imatinib resistance in GIST.
- Exploiting the mechanisms of imatinib-induced quiescence could lead to more effective treatment regimens for GIST patients.
- Interfering with quiescence pathways may enhance the efficacy of imatinib therapy, leading to better patient outcomes.
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