Abstract 4902: Oxidized low-density lipoprotein is a potentially potent mediator of proteasome inhibitor resistance in multiple myeloma

Abstract

Abstract Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow. While treatment advances, particularly proteasome inhibitors (PIs) and immunomodulatory drugs, have improved survival, MM is incurable. Obesity and insulin resistance are established risk factors for MM mortality. Oxidized low-density lipoprotein (OxLDL), a key atherogenic factor that is elevated in obesity, has emerged as a risk factor for the development and progression of some solid cancers, and it has been shown to stimulate pro-oncogenic signaling; its role in MM is unexplored. We evaluated the influence of OxLDL on MM cell killing by chemotherapeutics used to treat MM. OxLDL, at concentrations within the range reported for patients with metabolic syndrome, suppressed MM cell killing by the therapeutic PIs bortezomib and ixazomib. Native low-density lipoprotein (nLDL) did not affect the anti-MM effects of these PIs, which suggests that the oxidative modification of lipids or apolipoprotein in OxLDL is the mediator of cytoprotection. OxLDL did not affect MM cell killing by other agents with distinct targets such as the immunomodulatory drug lenolinamide and doxorubicin. OxLDL appeared to restore proteasome activity as evidenced by its suppression of bortezomib-induced accumulation of ubiquinated proteins and pro-apoptotic unfolded protein response signaling. The cytoprotective effects of OxLDL were suppressed when lipid hydroperoxides (LOOHs) associated with the lipoprotein were specifically reduced by pretreatment with the glutathione-dependent selenoperoxidase mimetic ebselen. Finally, immunohistochemical analysis of bone marrow biopsy samples from newly diagnosed MM patients demonstrated the presence of OxLDL in macrophages/histiocytes scattered among MM cells. Our findings suggest that OxLDL may be a potent mediator of chemoresistance to therapeutic PIs in obese/insulin-resistant MM patients. OxLDL appears to counteract the anti-MM effects of PIs through LOOH-mediated restoration of proteasome activity, which is significant since LDL is the major carrier of LOOHs in the plasma. Our findings raise the potential benefit of LDL cholesterol-lowering therapy, or pharmacologic targeting of intracellular pathways used by OxLDL, to increase the efficacy of therapeutic PIs and improve the survival of obese/insulin-resistant MM patients. Citation Format: Edward A. Medina, Javier Esparza, Srikanth Polusani, Valerie Cortez, Huynh N. Nguyen, Gopalrao V. Velagaleti, Hongxin Fan Fan, Marsha C. Kinney, Reto Asmis. Oxidized low-density lipoprotein is a potentially potent mediator of proteasome inhibitor resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4902.