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MULTIPLE MYELOMA, GAMMOPATHIES

Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma

Leukemia volume 39, pages 720–733 (2025)Cite this article

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Abstract

Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA levels caused by genetic or pharmacological inhibition of VLCFA degradation reduced the activity of two major kinases involved in MM pathogenesis, MET proto-oncogene (MET) and insulin-like growth factor 1 receptor (IGF1R). Mechanistically, inhibition of ACOX1 promoted the accumulation of VLCFA-containing cerebrosides, altered MET and IGF1R interaction with a cerebroside analog, and selectively inhibited the association of these kinases with the plasma membrane signaling platforms, importantly, without disrupting the platforms’ integrity. Our study revealed a specific metabolic vulnerability of MM cells and identified a targetable axis linking VLCFA metabolism to the regulation of MET and IGF1R activity.

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Fig. 1: ELOVL1 inhibition ameliorates BTZ cytotoxicity in MM cells.
Fig. 2: ABCD1 suppression cooperates with BTZ in MM cells.
Fig. 3: Genetic or pharmacological inhibition ACOX1 cooperates with BTZ in MM cells.
Fig. 4: Pharmacological inhibition ACOX1 cooperates with BTZ in suppressing MM cell xenograft growth.
Fig. 5: TDYA alters sphingolipid VLCFA composition, activity of MET and IGF1R, their association with DRMs and interactions with cerebroside analog.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

This work was supported by the National Institutes of Health, National Cancer Institute grants R01CA264984 (MAN), R21CA280499 (YK), P30CA014236 (Duke Cancer Institute), and the Paula and Rodger Riney Foundation (LHB), and Duke Functional Genomics Core Facility. Junqi Lu was a recipient of the 2023 Duke Master Student Biomedical Engineering Research Fellowship.

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Authors and Affiliations

  1. Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA

    Zhannan Han, Zhibo Yan, Yihui Wang, Maja Beus, Loren B. Weidenhammer, John D. Civils & Mikhail A. Nikiforov

  2. Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA

    Zhehan Ma, Junqi Lu & Mikhail A. Nikiforov

  3. Department of Hematology and Medical Oncology Emory School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA

    Kiran Lakhani & Lawrence H. Boise

  4. Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA

    Jingyun Lee & Cristina M. Furdui

  5. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA

    Liang Liu

  6. Division of Hematologic Malignancies & Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Jian Wu & Yubin Kang

  7. Department of Physiology, University of Kentucky College of Medicine, 741 S. Limestone BBSRB Room 269, Lexington, KY, 40536, USA

    Erhard Bieberich

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  1. Zhannan Han
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Contributions

ZH designed and performed most of the experiments and analyzed data; ZY, ZM, MB designed and performed experiments and analyzed data; YW, LBW performed experiments and analyzed data; JL performed statistical analysis; KL, LL and JW analyzed clinical data; JL performed lipidomic analysis and analyzed data; JDC performed experiments; CMF designed experiments and supervised data analysis; YK and EB designed experiments and helped write the manuscript; LHB designed experiments, supervised data analysis and helped write the manuscript; MAN conceived the study, designed experiments, supervised data analysis and wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Mikhail A. Nikiforov.

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The author declares no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. The study was approved by the Duke University Health System Institutional Review Board (IRB protocol #: Pro00006268) and the Wake Forest University Institutional Review Board (IRB protocol #: IRB00059639). All patients provided written informed consent. All animal experiments were approved by the Duke Institutional Animal Care and Use Committee (IACUC protocol #: A227-21-11-24).

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Han, Z., Yan, Z., Ma, Z. et al. Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma. Leukemia 39, 720–733 (2025). https://doi.org/10.1038/s41375-025-02522-9

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