慢性骨髓性白血病(CML)是一种克隆性骨髓增殖性疾病,其特征是存在融合癌基因BCR-ABL,其编码具有组成型TK活性的蛋白质。酪氨酸激酶抑制剂(TKIs)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,当在大多数对TKI实现完全分子应答的患者中停用这些药物时发生复发,而这些药物在具有BCR-ABL激酶结构域突变的患者中效果较差.重要的是,TKI能有效靶向增殖成熟细胞,但不能根除静止的白血病干细胞(LSCs),因此,尽管治疗,但仍允许疾病持续存在。至关重要的是,使用替代策略来针对LSC人群。BCR-ABL激活负责调节不同的信号通路,这允许LSC部分逃避细胞死亡。已显示几种途径受BCR-ABL调节,包括PI3K/AKT/mTOR,JAK-STAT和自噬信号通路。靶向这些生存途径的组成部分,单独或与TKI组合,因此代表了靶向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是活跃的。因此,必须验证潜在的靶标才能有效根除CML干细胞,同时避免正常的对应物。本文综述了CML干细胞调控的主要通路,最近的发展和使用新药靶向这些途径中的成分,这些途径可能用于靶向LSC群体。
背景:本文是关于肿瘤学中新兴治疗方面的主题部分的一部分。要查看本节中的其他文章,请访问http://dx。doi.org/10.1111/bph.2013.169。问题-8.
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.
BACKGROUND: 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.