Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors.
Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors.
复制标题
DOI：
10.1016/j.hoc.2017.04.007
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Deininger MW
中科院分区：
文献类型：
--
作者：
Patel AB;O'Hare T;Deininger MW
在美国，每年有超过8000例新的慢性粒细胞白血病（CML）确诊病例1。BCR-ABL 1是一种融合蛋白激酶，来源于9号和22号染色体之间的相互易位，是CML发病所必需和充分的。BCR-ABL 1的酪氨酸激酶抑制剂（TKI）彻底改变了CML治疗，预期寿命现已接近普通人群3。因此，CML的患病率正在增长，因为TKI患者越来越多地被视为慢性疾病，而不是潜在的致命疾病。据估计，超过25%的CML患者在其一生中至少会因TKI不耐受或耐药而更换一次TKI 4。BCR-ABL 1激酶结构域（KD）突变是CML中TKI耐药的最广泛研究机制，但无法解释20-40%的耐药病例。在这些病例中，替代的、BCR-ABL 1非依赖性生存途径的激活在机制上受到影响，也可以解释未能清除微小残留病变（MRD）或尽管达到了深度分子学缓解（DMR，国际量表上BCR-ABL 1 ≤ 0.01%，IS）但在停止治疗后复发的缓解患者中持续存在的现象。
Every year, more than 8000 new cases of chronic myeloid leukemia (CML) are diagnosed in the United States1. BCR-ABL1, a fusion protein kinase derived from a reciprocal translocation between chromosomes 9 and 22, is necessary and sufficient for CML pathogenesis2. Tyrosine kinase inhibitors (TKIs) of BCR-ABL1 have revolutionized CML therapy, with life expectancy now close to that of the general population3. As a result, the prevalence of CML is growing, as patients on TKIs live with what is more and more viewed as a chronic ailment rather than a potentially lethal disease. It is estimated that over 25% of CML patients will switch TKIs at least once during their lifetime due to TKI intolerance or resistance4. Mutations in the kinase domain (KD) of BCR-ABL1 are the most extensively studied mechanism of TKI resistance in CML, but fail to explain anywhere from 20–40% of resistant cases. Activation of alternative, BCR-ABL1-independent survival pathways has been mechanistically implicated in these cases, and may also explain the phenomenon of persistence in responding patients who fail to clear minimal residual disease (MRD) or experience recurrence upon discontinuation of therapy despite achieving deep molecular response (DMR, BCR-ABL1≤ 0.01% on the international scale, IS).
登录
查看更多内容
影响因子：
15.9
作者：
Chen, Yaoyu;Peng, Cong;Li, Shaoguang
通讯作者：
Li, Shaoguang
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
影响因子：
2.9
作者：
Eide, Christopher A.;O'Hare, Thomas
通讯作者：
O'Hare, Thomas
影响因子：
28.2
作者：
Asmussen J;Lasater EA;Tajon C;Oses-Prieto J;Jun YW;Taylor BS;Burlingame A;Craik CS;Shah NP
通讯作者：
Shah NP
影响因子：
10.1
作者：
Borthakur, Gautam;Dombret, Herve;Cortes, Jorge E.
通讯作者：
Cortes, Jorge E.