Fatty acid binding proteins contribute to multiple myeloma cell maintenance through regulation of Myc, the unfolded protein response, and metabolism

Multiple myeloma (MM) is an incurable plasma cell malignancy that causes anemia, osteolysis, hypercalcemia, and organ failure, with only a 53% 5-years survival rate. Herein, we present data demonstrating a novel target in MM: the fatty acid binding protein (FABP) family. In clinical data, FABP5 represented a novel biomarker for more aggressive cancer. FABP inhibitors decreased tumor burden in vitro and in vivo and increased survival in immunocompetent and immunocompromised mouse models. FABP5 was the most highly expressed FABP member in myeloma cells, and the most essential for their survival. CRISPR-Cas9 generated FABP5-KO MM.1S cells showed inhibited growth potential. RNA-sequencing and metabolic analysis identified new pathways of action for the FABPs, including MYC, the unfolded protein response (UPR), and metabolic changes. Collectively, our results demonstrate that FABPs comprise a novel, targetable, and safe, therapeutic avenue for MM and other cancers, and suggest inhibiting FABPs may be worthy of further study. MM.1S cells were cultured for 24 hours with 50 μM BMS309403, 50 μM SBFI-26 or the combination in a T25 at a density of 2.5x10^6 cells. mRNA was isolated with Qiazol and miRNeasy Mini Kit with on-column DNAse digestion according to the manufacturer’s protocol.