Tolland Molly, Ross David M, White Deborah, Hughes Timothy P, Pagani Ilaria S
Precision Cancer Medicine Theme, Blood Cancer Program, South Australian Health & Medical Research Institute, Adelaide 5000, Australia.
School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5000, Australia.
Cancers (Basel). 2025 Sep 17;17(18):3033. doi: 10.3390/cancers17183033.
While there have been outstanding improvements in the treatment of Chronic Myeloid Leukaemia (CML), some patients do not respond optimally or are entirely resistant to treatment. In many of these patients, the molecular basis for resistance to tyrosine kinase inhibitors (TKIs) is unknown, highlighting the need for further investigation. Various potential mechanisms of TKI resistance are being explored with the aim of identifying new therapeutic options. A growing body of evidence suggests that alterations in lipid metabolism are implicated in treatment resistance in a variety of cancers including CML. Intracellular lipid storage may play a protective role to facilitate drug resistance in cancers and subsequently could serve as a targetable vulnerability. Due to the single genetic driver of oncogenesis, CML is an excellent model disease for studying metabolic alterations in cancer that contribute to drug resistance and disease progression. Based on the need to identify adjuvant therapies for TKI-resistant CML, we have evaluated evidence of dysregulated lipid storage in CML and its potential as a therapeutic target. In addition to in vitro analysis, we discuss the outcomes of clinical studies of CML treated with therapeutics that target lipid storage both directly and indirectly. We also highlight key limitations in the current literature and identify priority areas for further investigation. Advancing our understanding of lipid metabolic pathways, including lipid storage, in CML may reveal actionable vulnerabilities and support the development of novel therapeutic strategies to overcome TKI resistance.
虽然慢性髓性白血病（CML）的治疗已经有了显著改善，但一些患者对治疗的反应并不理想或完全耐药。在许多这类患者中，对酪氨酸激酶抑制剂（TKIs）耐药的分子基础尚不清楚，这凸显了进一步研究的必要性。目前正在探索TKI耐药的各种潜在机制，目的是确定新的治疗选择。越来越多的证据表明，脂质代谢改变与包括CML在内的多种癌症的治疗耐药有关。细胞内脂质储存可能起到保护作用，促进癌症中的耐药性，随后可作为一个可靶向的弱点。由于致癌作用的单一基因驱动因素，CML是研究癌症中导致耐药和疾病进展的代谢改变的理想模型疾病。基于确定TKI耐药CML辅助治疗的需要，我们评估了CML中脂质储存失调的证据及其作为治疗靶点的潜力。除了体外分析，我们还讨论了直接和间接靶向脂质储存的疗法治疗CML的临床研究结果。我们还强调了当前文献中的关键局限性，并确定了进一步研究的优先领域。加深我们对CML中脂质代谢途径（包括脂质储存）的理解，可能会揭示可操作的弱点，并支持开发克服TKI耐药性的新治疗策略。
