MULTIPLE MYELOMA (MM), an incurable blood cancer, remains a major challenge in oncology, with a pressing need for novel treatment strategies. A new study has identified a significant metabolic vulnerability in MM cells linked to very long chain fatty acids (VLCFAs), which could pave the way for more effective therapies.
Researchers found that intracellular VLCFAs control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced the cell death caused by bortezomib, a commonly used proteasome inhibitor. However, inhibiting the degradation of VLCFAs—by suppressing peroxisomal acyl-CoA oxidase 1 (ACOX1)—increased the effectiveness of bortezomib, as well as its next-generation analogue, carfilzomib, and the immunomodulatory drug lenalidomide.
Moreover, treatment with an oral ACOX1 inhibitor successfully enhanced the anti-cancer effects of bortezomib in mice with bortezomib-resistant MM xenografts. This highlights the potential of targeting VLCFA metabolism as a therapeutic strategy in resistant cases.
Mechanistically, the study revealed that VLCFA accumulation disrupted the interaction of two key kinases, MET and IGF1R, involved in MM pathogenesis. By altering their binding to cerebrosides, ACOX1 inhibition selectively prevented the kinases from associating with critical membrane signalling platforms, without damaging the platforms themselves.
This research uncovers a previously unknown metabolic vulnerability in MM, offering new avenues for therapeutic intervention by targeting VLCFA metabolism to enhance existing treatments and potentially overcome drug resistance.
Helena Bradbury, EMJ
Reference
Han Z et al. Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma. Leukemia. 2025; doi: 10.1038/s41375-025-02522-9.
