Han Zhannan, Yan Zhibo, Ma Zhehan, Wang Yihui, Beus Maja, Lu Junqi, Weidenhammer Loren B, Lakhani Kiran, Lee Jingyun, Civils John D, Furdui Cristina M, Liu Liang, Wu Jian, Kang Yubin, Bieberich Erhard, Boise Lawrence H, Nikiforov Mikhail A
Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA.
Leukemia. 2025 Mar;39(3):720-733. doi: 10.1038/s41375-025-02522-9. Epub 2025 Jan 30.
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.
多发性骨髓瘤（MM）仍然是一种无法治愈的血液系统恶性肿瘤，因此需要确定新的治疗策略。在此，我们报告超长链脂肪酸（VLCFA）的细胞内水平控制着MM化疗药物的细胞毒性。抑制VLCFA生物合成可减少蛋白酶体抑制剂硼替佐米引起的MM细胞死亡。相反，通过抑制过氧化物酶体酰基辅酶A氧化酶1（ACOX1）来抑制VLCFA降解，可增强硼替佐米、其下一代类似物卡非佐米以及免疫调节剂来那度胺的细胞毒性。此外，口服可用的ACOX1抑制剂与硼替佐米联合使用，可抑制硼替佐米耐药的MM异种移植物在小鼠体内的生长。由VLCFA降解的基因或药理学抑制引起的VLCFA水平升高，降低了MM发病机制中涉及的两种主要激酶，即原癌基因MET和胰岛素样生长因子1受体（IGF1R）的活性。从机制上讲，抑制ACOX1促进了含VLCFA的脑苷脂的积累，改变了MET和IGF1R与脑苷脂类似物的相互作用，并有选择地抑制了这些激酶与质膜信号平台的结合，重要的是，没有破坏平台的完整性。我们的研究揭示了MM细胞的一种特定代谢脆弱性，并确定了一个可靶向的轴，将VLCFA代谢与MET和IGF1R活性的调节联系起来。
