Lipid Metabolism-driven Drug Resistance in Multiple Myeloma

Abstract Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells primarily in the bone marrow and has a 5-year survival rate of only 50%. Obesity increases the risk of MM incidence and predicts a poorer response to treatment. In fact, obesity is a major risk factor for many cancers, and there are likely an

array of mechanisms by which obesity supports cancer development and progression. One mechanism may be through the increased availability of free fatty acids, which are elevated in the plasma of obese people. Fatty acids can be used as a fuel source for cells through a process called fatty acid oxidation. Thus, based on

the role of fatty acid oxidation in other cancers, and the obesity risk factor in MM, we hypothesize that fatty acids and fatty acid oxidation contribute to MM progression. Myeloma cells are supported by many factors and cells in the bone marrow microenvironment. Interestingly, up to 70% of the bone marrow is composed of yellow

(fatty) marrow, which is increased in obesity, as well as aging (another major risk factor for MM). Yellow marrow is composed of bone marrow adipocytes (fat cells), which are often adjacent to myeloma cells. Our lab, and others, have shown that bone marrow adipocytes drive resistance to chemotherapeutic agents in myeloma

cells. Thus, we will test the hypothesis that fatty acid oxidation contributes to myeloma cell survival and drug resistance, and that bone marrow adipocytes support myeloma cell drug resistance through increasing their fatty acid oxidation, in the following two Aims. Aim 1) We will test the hypothesis that fatty acid oxidation

supports myeloma cells by inhibiting the rate-limiting enzyme for fatty acid oxidation, carnitine- palmitoyltransferase 1 (CPT1), through genetic or pharmacological methods, and measuring myeloma cell proliferation/death, respiration, metabolites, and responses to dexamethasone. To specifically test the roles of

certain lipids in fatty acid oxidation, we will investigate the changes in myeloma cell survival and drug resistance in response to lipids that are highly enriched in human serum and from bone marrow adipocytes. Aim 2) We will test the hypothesis that bone marrow adipocytes enhance myeloma cell fatty acid oxidation,

survival, and drug resistance by co-culturing myeloma cells lacking functional CPT1 as above, or controls, with bone marrow adipocytes and identifying how myeloma cells respond and metabolize bone marrow adipocyte- derived fatty acids. Taken together, these experiments will elucidate the mechanisms of how bone marrow

adipocytes and fatty acid oxidation affect myeloma cell survival and drug resistance.