Departments of Pharmacology and Toxicology, College of Pharmacy, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Cancer J. 2011 Nov-Dec;17(6):477-86. doi: 10.1097/PPO.0b013e318237e5b7.
Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5' triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment modalities that are under development. Recent advances have illuminated the complexity of CML, especially within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL because primitive human CML stem cells are not dependent on BCR-ABL. Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML.
在过去的十年中，靶向小分子药物彻底改变了慢性髓性白血病（CML）的治疗方法。这些药物通过干扰依赖于腺苷 5'三磷酸的 ABL 酪氨酸激酶，来阻断慢性髓性白血病的致病因素——持续激活的 BCR-ABL。虽然酪氨酸激酶抑制剂（TKI）的疗效使总体生存率超过 90%，但 TKI 并不能治愈疾病。此外，目前没有批准的 TKI 对 T315I BCR-ABL 变体有效。然而，新一代针对 T315I 的 TKI 即将问世。我们将重点介绍 CML 治疗的历史、当前使用的治疗方法（第一代和第二代 TKI），并讨论正在开发的治疗方式。最近的进展揭示了 CML 的复杂性，尤其是骨髓微环境中的复杂性。我们认为，治愈 CML 的关键将涉及超越 BCR-ABL 靶点的策略，因为原始的人类 CML 干细胞并不依赖于 BCR-ABL。最终，药物联合或利用合成致死性可能会将反应转化为 CML 的确定性治愈方法。
