The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses.
aDepartment 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.
James A
JA
DeCaprio
Anette
A
Duensing
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D050704:E2F4 Transcription Factor / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D058990:Molecular Targeted Therapy / Q000379:methods; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D050717:Retinoblastoma-Like Protein p130 / Q000502:physiology
D000970:Antineoplastic Agents; D001549:Benzamides; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C493837:RBL2 protein, human; D050717:Retinoblastoma-Like Protein p130; D000068877:Imatinib Mesylate