期刊
CANCER JOURNAL
卷 17, 期 6, 页码 477-486出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/PPO.0b013e318237e5b7
关键词
Chronic myeloid leukemia; BCR-ABL; tyrosine kinase inhibitors; drug resistance; synthetic lethality
类别
资金
- National Institutes of Health [HL082978-01, CA04963920A2, CA129528]
- Leukemia and Lymphoma Society [7036-01]
- Howard Hughes Medical Institute through Med into Grad Initiative
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.
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