慢性髓性白血病中对ABL激酶抑制的耐药机制及下一代ABL激酶抑制剂的研发
Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors.
作者信息
Patel Ami B, O'Hare Thomas, Deininger Michael W
机构信息
Department of Hematology and Oncology, Huntsman Cancer Institute, 2000 Circle of Hope Drive, The University of Utah, Salt Lake City, UT 84112, USA.
Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA.
出版信息
Hematol Oncol Clin North Am. 2017 Aug;31(4):589-612. doi: 10.1016/j.hoc.2017.04.007.
Abstract
Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1-dependent and BCR-ABL1-independent mechanisms continues to be an issue. BCR-ABL1-dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1-independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy.
摘要
慢性髓性白血病越来越被视为一种慢性疾病；大多数患者的预期寿命接近普通人群。尽管使用BCR-ABL1酪氨酸激酶抑制剂（TKIs）取得了进展，但通过BCR-ABL1依赖性和BCR-ABL1非依赖性机制产生的耐药性仍然是一个问题。BCR-ABL1依赖性耐药主要通过癌蛋白激酶结构域突变介导，通常导致对TKIs的明显耐药。然而，在有效的BCR-ABL1抑制情况下，BCR-ABL1非依赖性耐药被认为是微小残留病的主要促成因素。根除持续存在的白血病干细胞的努力集中在联合治疗上。
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