Serkova Natalie, Boros László G
Department of Anesthesiology, Biomedical MRS/MRI Cancer Core, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Am J Pharmacogenomics. 2005;5(5):293-302. doi: 10.2165/00129785-200505050-00002.
Acquired resistance to imatinib mesylate is an increasing and continued challenge in the treatment of BCR-ABL tyrosine kinase positive leukemias as well as gastrointestinal stromal tumors. Stable isotope-based dynamic metabolic profiling (SIDMAP) studies conducted in parallel with the development and clinical testing of imatinib revealed that this targeted drug is most effective in controlling glucose transport, direct glucose oxidation for RNA ribose synthesis in the pentose cycle, as well as de novo long-chain fatty acid synthesis. Thus imatinib deprives transformed cells of the key substrate of macromolecule synthesis, malignant cell proliferation, and growth. Tracer-based magnetic resonance spectroscopy studies revealed a restitution of mitochondrial glucose metabolism and an increased energy state by reversing the Warburg effect, consistent with a subsequent decrease in anaerobic glycolysis. Recent in vitro SIDMAP studies that involved myeloid cells isolated from patients who developed resistance against imatinib indicated that non-oxidative ribose synthesis from glucose and decreased mitochondrial glucose oxidation are reliable metabolic signatures of drug resistance and disease progression. There is also evidence that imatinib-resistant cells utilize alternate substrates for macromolecule synthesis to overcome limited glucose transport controlled by imatinib. The main clinical implications involve early detection of imatinib resistance and the identification of new metabolic enzyme targets with the potential of overcoming drug resistance downstream of the various genetic and BCR-ABL-expression derived mechanisms. Metabolic profiling is an essential tool used to predict, clinically detect, and treat targeted drug resistance. This need arises from the fact that targeted drugs are narrowly conceived against genes and proteins but the metabolic network is inherently complex and flexible to activate alternative macromolecule synthesis pathways that targeted drugs fail to control.
对甲磺酸伊马替尼产生获得性耐药是BCR-ABL酪氨酸激酶阳性白血病以及胃肠道间质瘤治疗中日益严峻且持续存在的挑战。在伊马替尼的研发和临床试验过程中同时开展的基于稳定同位素的动态代谢谱分析（SIDMAP）研究表明，这种靶向药物在控制葡萄糖转运、戊糖循环中用于RNA核糖合成的直接葡萄糖氧化以及从头合成长链脂肪酸方面最为有效。因此，伊马替尼剥夺了转化细胞中大分子合成、恶性细胞增殖和生长的关键底物。基于示踪剂的磁共振波谱研究表明，通过逆转瓦伯格效应恢复了线粒体葡萄糖代谢并提高了能量状态，这与随后无氧糖酵解的减少一致。最近涉及从对伊马替尼产生耐药性的患者中分离出的髓样细胞的体外SIDMAP研究表明，葡萄糖的非氧化核糖合成减少以及线粒体葡萄糖氧化减少是耐药和疾病进展的可靠代谢特征。也有证据表明，对伊马替尼耐药的细胞利用替代底物进行大分子合成，以克服伊马替尼控制的有限葡萄糖转运。主要的临床意义包括早期检测伊马替尼耐药性以及鉴定具有克服各种遗传和BCR-ABL表达衍生机制下游耐药性潜力的新代谢酶靶点。代谢谱分析是用于预测、临床检测和治疗靶向药物耐药性的重要工具。之所以有这种需求，是因为靶向药物针对的是基因和蛋白质，但代谢网络本质上是复杂且灵活的，能够激活靶向药物无法控制的替代大分子合成途径。
