Abstract 1127: Bcr-Abl inhibition in leukemia cells creates metabolic addictions

Abstract

Abstract Bcr-Abl kinase inhibitors are the standard therapy for chronic myelogenous leukemia (CML). While effective in controlling disease in chronic phase, these inhibitors often fail to completely eliminate Bcr-Abl+ CML cells and also fail to achieve durable remissions for advanced CML and Bcr-Abl+ acute lymphoblastic leukemias (ALL). Our lab employed a large-scale synthetic lethal shRNA screen to identify genes involved in CML survival upon treatment with the Bcr-Abl kinase inhibitor imatinib (IM) [Cancer Cell. 2010;18(1):74-87]. This screen identified several genes involved in energy utilization including a component of pyruvate dehydrogenase, dihydrolipoyllysine-residue acetyltransferase. CML proliferation depends on Bcr-Abl-driven glycolysis for energy production. Upon IM treatment, we hypothesized that these cells are forced to rely on other sources of energy including the TCA cycle and the electron transport chain, and that targeting alternative energy production pathways will enhance IM-mediated elimination of CML cells. Thus, we predicted that inhibition of mitochondrial respiration by knockdown or pharmacologic inhibition would cooperate with tyrosine kinase inhibitors (TKI) to eliminate Bcr-Abl+ leukemia. Indeed, our experiments have shown that knocking down pyruvate dehydrogenase in human blast crisis Bcr-Abl+ CML cells (K562) greatly sensitized cells to IM in vitro. Conversely, supplementing the cell culture media with increasing concentrations of methyl-pyruvate protected K562 cells from IM treatment. Moreover, we found that the mitochondrial ATP-synthase inhibitor Oligomycin A (OA) also synergized with IM to kill CML cells in vitro. Interestingly, the doses of OA are far below the IC50 and do not affect the oxygen consumption rates, indicating that mitochondrial respiration is not inhibited. These OA doses alter mitochondrial transmembrane potential and increasing superoxide levels. In addition, OA enhanced elimination of Bcr-Abl+ cells by a Bcr-Abl TKI in vivo and prolonged disease-free survival in a mouse model of Bcr-Abl+ B-ALL. Notably, drug doses of OA used had no apparent adverse effects on these mice. Targeting mitochondrial metabolism as an adjuvant drug therapy may prevent the survival of residual Bcr-Abl+ CML cells upon tyrosine kinase inhibitor treatment. This project is supported by pre-doctoral fellowship number F31CA157166 from the National Cancer Institute, and Leukemia and Lymphoma Society Grant Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1127. doi:1538-7445.AM2012-1127