Abstract 665: Targeting the pro-apoptotic protein BIM by dexamethasone combined with a MEK inhibitor PD184352 enhances the lethality in acute lymphoblastic leukemia

Abstract

Abstract Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). Although the effects of GC on lymphocytes have been scrutinized for many years, the molecular mechanisms of sensitivity and resistance need to be elucidated. Since GC-resistant leukemia and myeloma are often associated with GC receptor defects, bypassing the receptor by targeting downstream molecules may develop new therapeutic strategies. We and others have previously shown that BIM (BCL-2 Interacting Mediator of cell death), a pro-apoptotic BCL-2 family protein, is up-regulated by dexamethasone (Dex) treatment in ALL cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation by survival/growth factors. We therefore hypothesized that co-treatment with Dex and MEK/ERK inhibitors promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. We have recently demonstrated that MEK inhibitors synergistically promote Dex lethality in a variety of ALL cell lines, in which BIM is a critical molecule in cell death (Rambal et al., Leukemia 23, 1744-1754, 2009). In the present study, we examined the therapeutic potential of co-treatment of Dex and MEK inhibitor PD184352 in vivo by severe combined immunodeficiency (SCID) mouse xenograft models of ALL. Minimum doses of Dex (8 mg/kg/day) and PD184352 (50 mg/kg/day) treatment caused BIM up-regulation and ERK dephosphorylation in xenograft tumor samples, respectively. Co-treatment of Dex and PD184352 resulted in an increase of apoptosis determined by caspase-3 cleavage and a significant decrease in size of the tumors. These data show that MEK/ERK inhibition enhances the anti-tumor activity of Dex in vivo. Our study provides a rational foundation for future attempts to improve the effect of GC with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 665.