Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Division of Tumor Immunology, Center for Hematologic Malignancies, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
Int J Hematol. 2021 May;113(5):632-641. doi: 10.1007/s12185-021-03126-6. Epub 2021 Mar 27.
BCR-ABL1 plays a key role in the pathogenesis of chronic myeloid leukemia (CML), and it has been investigated as a druggable target of tyrosine kinase inhibitors (TKIs) over two decades. Since imatinib, the first TKI for anti-cancer therapy, was successfully applied in CML therapy, further generation TKIs and a novel allosteric inhibitor targeting the myristate binding site have been developed as alternative options for CML management. However, significant concerns regarding toxicity profiles, especially in long-term treatment, have emerged from TKI clinical data. Efforts to reduce adverse events and serious complications are warranted not only for survival, but also quality of life in CML patients. A better understanding of the mechanism of action will help to identify on- and off-target effects of TKIs, and guide personalized TKI drug selection in each individual CML patient. Herein, this review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.
BCR-ABL1 在慢性髓细胞白血病 (CML) 的发病机制中起着关键作用，二十多年来，它一直被作为酪氨酸激酶抑制剂 (TKI) 的可用药靶点进行研究。自伊马替尼（用于癌症治疗的第一种 TKI）成功应用于 CML 治疗以来，进一步开发了新一代 TKI 和一种针对豆蔻酸结合位点的新型变构抑制剂，作为 CML 管理的替代选择。然而，TKI 临床数据显示，毒性特征，特别是在长期治疗中，引起了人们的高度关注。减少不良事件和严重并发症的努力不仅对生存，而且对 CML 患者的生活质量都是必要的。更好地了解作用机制将有助于确定 TKI 的靶内和靶外作用，并指导每个 CML 患者的个体化 TKI 药物选择。本文综述了 BCR-ABL1 抑制和不同靶谱的生物学机制，以及每种 TKI 的相关脱靶效应。
