The goal of this proposal is to establish pre-clinical evidence of synergism between glucocorticoids such as dexamethasone (Dex) and the MEK inhibitors such as PD184352 in the induction of apoptosis in acute lymphoblastic leukemia (ALL) cells. Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including ALL. GC-induced apoptosis involves the intrinsic mitochondria-dependent pathway, but the signaling pathways and downstream target molecules involved in GC-induced cell death are not entirely clear. 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 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 hypothesize that co-treatment with Dex and MEK/ERK inhibitors will promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. Significantly, preliminary data from our laboratory demonstrate that MEK inhibitors synergistically promote DEX lethality in a variety of ALL cell lines. We now propose to elucidate the mechanisms by which MEK/ERK inhibition enhances the activity of BIM and perturbs other pro- and anti-apoptotic BCL-2 family members to enhance Dex efficacy in ALL cells.
The specific aims are to 1) evaluate the significance of BIM-dependent/-independent pathways and the BIM phosphorylation status in apoptosis with Dex and MEK inhibitors co-treatment;2) determine the molecular mechanisms how BIM is induced by dexamethasone treatment;3) employ in vivo murine models of ALL to establish a basis for the efficacy of the strategy. The main concept is that we have a novel and potentially effective way to increase GC activity against leukemia cells, which may reflect the fact that a) GCs up-regulate BIM;and b) pharmacologic MEK inhibitors further potentiate BIM activation by blocking BIM phosphorylation and degradation. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as dexamethasone with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page
The main concept is that we have a novel and potentially effective way to increase glucocorticoids (GC) activity against acute lymphoblastic leukemia (ALL) cells, which may reflect the fact that a) GC up-regulate a pro-death molecule, BIM;and b) pharmacologic MEK/ERK inhibitors further potentiate BIM activation. In this proposal, we will establish the mechanistic evidence how MEK/ERK-BIM pathway involves the synergistic interaction of dexamethasone (Dex) and MEK/ERK inhibitors. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as Dex with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.
