The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

Background Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate, highlighting a critical need for new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. Methods Myeloma cells treated with FABP inhibitors (BMS3094013 and SBFI-26) were examined in vivo and in vitro for cell cycle, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation. Myeloma cell responses to BMS309403 and/or SBFI-26 were assessed with RNA-sequencing and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using DepMap. Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. Results Myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation in vitro . FABPi had potent anti- tumor effects both in vitro and in vivo in two pre-clinical MM mouse models where increased mouse survival was observed. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 . Conclusions This study establishes the FABP family as a therapeutically actionable dependency in multiple myeloma with a multitude of actions and cellular roles that result in the support of myeloma progression. Statement of translational relevance Multiple myeloma (MM) is an incurable disease of the plasma cell and MM patients require better treatments as soon as possible. The fatty acid binding protein (FABP) family plays a number of roles in cells, including supporting fatty acid oxidation, lipid shuttling and signal transduction. Here, we demonstrate with CoMMpass and other clinical data that FABPs represent a biomarker for aggressive disease in MM, and are a novel, targetable protein family expressed by myeloma cells. Pharmacologically inhibiting FABPs kills tumor cells and induces cell cycle arrest in vitro and in pre-clinical models. Mechanisms of action are multitudinous, as we discovered with RNA-sequencing, proteomic analysis, and phenotyping assays. Cell metabolism, cell signaling, cell stress, and epigenetic signatures were altered in MM cells when FABPs were inhibited. In summary, targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells. ### Competing Interest Statement Marinac:?GRAIL Inc: Research Funding; JBF Legal: Consultancy. Reagan: Oncopeptides Inc, SynDevRx Inc: Research Funding. All other authors declare no COI.