文章：

突破慢性髓性白血病靶向治疗的极限

Pushing the limits of targeted therapy in chronic myeloid leukaemia

原文发布日期：2012-07-24

DOI: 10.1038/nrc3317

类型: Review Article

开放获取: 否

要点：

1. Small-molecule BCR-ABL1 tyrosine kinase inhibitors (TKIs) have fundamentally improved the treatment of chronic myeloid leukaemia (CML) and have become a paradigm for molecularly targeted therapy, but they fail to kill leukaemic stem cells (LSCs).
2. BCR-ABL1-dependent resistance to currently approved TKIs typically involves single point mutations within the BCR-ABL1 tyrosine kinase domain that interfere with drug binding.
3. Third-generation TKIs that comprehensively cover single BCR-ABL1 mutants, including the T315I mutant (BCR-ABL1^T315I), are in development. With respect to resistance, these TKIs are vulnerable to certain compound mutations (two or more mutations in the same BCR-ABL1 molecule) in in vitro model systems. The extent to which BCR-ABL1 compound mutation-based resistance tempers the effectiveness of third-generation TKIs in the clinical setting remains to be established.
4. BCR-ABL1-independent TKI resistance occurs despite effective inhibition of BCR-ABL1 kinase activity.
5. CML stem cells may rely on pathways similar to those responsible for BCR-ABL1-independent TKI resistance.
6. Other crucial targets in addition to BCR-ABL1 will probably need to be inhibited in both cases. Candidate pathways include Hedgehog, WNT–β-catenin, PP2A and transforming growth factor-β (TGFβ)–Forkhead box protein O3 (FOXO3A)–BCL-6.

要点翻译：

1. 小分子BCR-ABL1酪氨酸激酶抑制剂（TKIs）从根本上改善了慢性髓系白血病（CML）的治疗，并已成为分子靶向治疗的典范，但它们无法消灭白血病干细胞（LSCs）。
2. 目前获批TKIs的BCR-ABL1依赖性耐药通常涉及BCR-ABL1酪氨酸激酶结构域内的单点突变，这些突变会干扰药物结合。
3. 能全面覆盖单BCR-ABL1突变体（包括T315I突变体BCR-ABL1T315I）的第三代TKIs正在研发中。在耐药性方面，这些TKIs在体外模型系统中易受某些复合突变（同一BCR-ABL1分子中存在两个或多个突变）的影响。基于BCR-ABL1复合突变的耐药性在临床环境中对第三代TKIs效果的削弱程度尚待明确。
4. 尽管有效抑制了BCR-ABL1激酶活性，仍会出现BCR-ABL1非依赖性TKI耐药。
5. CML干细胞可能依赖于与导致BCR-ABL1非依赖性TKI耐药相似的通路。
6. 在这两种情况下，可能还需要抑制除BCR-ABL1以外的其他关键靶点。候选通路包括Hedgehog、WNT–β-连环蛋白、PP2A以及转化生长因子-β（TGFβ）–叉头框蛋白O3（FOXO3A）–BCL-6。

英文摘要：

Tyrosine kinase inhibitor (TKI) therapy targeting the BCR-ABL1 kinase is effective against chronic myeloid leukaemia (CML), but is not curative for most patients. Minimal residual disease (MRD) is thought to reside in TKI-insensitive leukaemia stem cells (LSCs) that are not fully addicted to BCR-ABL1. Recent conceptual advances in both CML biology and therapeutic intervention have increased the potential for the elimination of CML cells, including LSCs, through simultaneous inhibition of BCR-ABL1 and other newly identified, crucial targets.

摘要翻译： 

酪氨酸激酶抑制剂（TKI）靶向BCR-ABL1激酶治疗慢性髓性白血病（CML）有效，但对大多数患者并非根治性。微小残留病（MRD）被认为存在于对TKI不敏感、并不完全依赖BCR-ABL1的白血病干细胞（LSCs）中。近年来，CML生物学和治疗干预的概念性进展，通过同时抑制BCR-ABL1及其他新发现的关键靶点，增加了根除CML细胞（包括LSCs）的可能性。

原文链接：

Pushing the limits of targeted therapy in chronic myeloid leukaemia