Abstract 972: Targeting glucose and glutamine regulated BCL2 family members for multiple myeloma therapy

Abstract

Abstract Multiple myeloma (MM) is a plasma cell malignancy accounting for approximately 11000 deaths annually in the US. Despite use of immunomodulatory drugs and proteasome inhibitors, MM is largely incurable with a median survival of 5 years due to the development of intrinsic and acquired resistance to these drugs. Targeting metabolic dependencies in a cancer cell may provide an effective strategy to target the molecular heterogeneity and chemo resistance characteristic of MM. Resistance is in part mediated by ineffective regulation of Bcl-2 family members. Myeloid cell leukemia factor 1 (MCL-1) is a key resistance promoting anti-apoptotic protein expressed in MM cells. We and others have previously established that glucose regulates expression of MCL-1. MM cells are heavily reliant upon glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. While glucose withdrawal was found to suppress MCL-1 expression uniformly, this did not always correlate with the extent of apoptosis induced. One potential mechanism for continued survival despite suppression of MCL-1 could be due to a shift in binding of pro-apoptotic BCL2 proteins to alternate pro-survival BCL2 members. Our investigation through co-immunoprecipitation experiments revealed that glucose or glutamine withdrawal enhances a shift in binding of pro-apoptotic BIM from MCL-1 to BCL2/ BCLxL. This shift in the association of BIM to BCL2 and BCLxL increased sensitivity to BH3 mimetics ABT-199/737. Induction of NOXA, that has a greater affinity for MCL-1 than BIM, is known to promote the redistribution of BIM to BCL2 and BCLxL. Indeed, glucose and glutamine withdrawal were found to increase NOXA expression associated with activation of the upstream GCN2/PERK/eIF2α/ATF4 axis in a cell type specific manner. Knock down of NOXA in MM cells successfully increased cell survival and reduced sensitivity towards ABT-199 in glucose or glutamine deprived cells. We have extended these observations to a panel of 7 myeloma cell lines and primary myeloma patient samples. Our study broadly divides MM cells into two subtypes on the basis of glucose or glutamine dependency and provides effective ways to their survival by targeting their specific metabolic dependencies in combination with the BH3 mimetic ABT-199. We also demonstrate that glucose transport and metabolism in MM can be targeted with the FDA approved GLUT4 inhibitor ritonavir and glutamine utilization can be inhibited by glutamine antagonist DON (6-Diazo-5-oxo-L-norleucine). Both ritonavir and DON treatments sensitized MM cell lines and primary patient samples to ABT-199, bolstering the utility of repurposing FDA-approved ritonavir and ABT-199 (in clinical trial) for MM therapy. Citation Format: Richa Bajpai, Shannon M. Matulis, Changyong Wei, Ajay K. Nooka, Lawrence H. Boise, Mala Shanmugam. Targeting glucose and glutamine regulated BCL2 family members for multiple myeloma therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 972. doi:10.1158/1538-7445.AM2015-972