Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Br J Pharmacol. 2013 Aug;169(8):1693-707. doi: 10.1111/bph.12183.
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population.
This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.
慢性髓性白血病（CML）是一种克隆性骨髓增殖性疾病，其特征是存在融合致癌基因 BCR-ABL，该基因编码一种具有组成性 TK 活性的蛋白质。酪氨酸激酶抑制剂（TKI）的实施标志着 CML 治疗的重大进展；然而，目前的治疗存在问题。例如，当大多数在 TKI 上达到完全分子反应的患者停止使用这些药物时，会发生复发，并且这些药物在 BCR-ABL 激酶结构域发生突变的患者中效果较差。重要的是，TKI 可以有效地针对增殖的成熟细胞，但不能根除静止的白血病干细胞（LSC），因此尽管进行了治疗，但仍允许疾病持续存在。使用替代策略来靶向 LSC 群体至关重要。BCR-ABL 的激活负责调节不同的信号通路，这允许 LSC 分数逃避细胞死亡。已经表明，包括 PI3K/AKT/mTOR、JAK-STAT 和自噬信号通路在内的几条通路受到 BCR-ABL 的调节。因此，单独或与 TKI 联合靶向这些存活途径的成分代表了针对 LSC 的有吸引力的潜在治疗方法。然而，许多途径在正常干细胞中也很活跃。因此，必须验证潜在的靶点，以有效地根除 CML 干细胞，同时保留正常的对应物。这篇综述总结了在 CML 干细胞中调节的主要途径、最近的发展以及使用新型药物靶向这些途径中的成分，这些成分可能用于靶向 LSC 群体。
本文是肿瘤学新兴治疗方面专题的一部分。要查看该部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2013.169.issue-8。
