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.
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
Correspondence to Anette Duensing, MD, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.8, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Tel: +1 412 623 5870; fax: +1 412 623 7715; e-mail: firstname.lastname@example.org