Targeting Fatty Acid Oxidation Pathways to Overcome Proteasome Inhibitor Resistance in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a blood cancer that affects plasma cells; despite recent significant advancements in therapy, the disease remains incurable with only a 53% 5-year survival rate. Given this grim reality, there is an urgent need to discover new vulnerabilities in MM and explore innovative therapeutic approaches. In this study, we investigated the possible anti-myeloma efficacy of a recently developed chemical inhibitor known as DIAPO (drug-inducing apoptosis). DIAPO has demonstrated the ability to trigger apoptosis in both treatment-naïve multiple myeloma cells and cells that have developed resistance to commonly used proteasome inhibitors such as bortezomib and carfilzomib. We used both in vitro and in vivo MM xenografts models to assess various cellular processes including cell viability, apoptosis, and cellular metabolism (specifically oxygen consumption rates and fatty acid oxidation). Mechanistically, we discovered that DIAPO inhibits crucial survival signalling pathways in proteasome inhibitor-resistant cells, particularly by suppressing the expression of key regulators of fatty acid oxidation. Our findings suggest that DIAPO could be a promising treatment for patients with multiple myeloma, particularly for those who have developed resistance to current standard therapies and provide a strong rationale for extending the preclinical and clinical testing of DIAPO to improve patient outcome in MM.