文章：

ABL家族激酶在癌症中的作用：从白血病到实体瘤

Role of ABL family kinases in cancer: from leukaemia to solid tumours

原文发布日期：2013-07-11

DOI: 10.1038/nrc3563

类型: Review Article

开放获取: 否

要点：

1. ABL1 was first discovered more than 30 years ago as the oncogene in the Abelson murine leukaemia virus and was later identified as an oncogene that is associated with chromosome translocations in human leukaemias. Recently, activation of ABL1 and ABL2 has been detected in solid tumours.
2. Activation of ABL kinases in solid tumours is driven by enhanced expression (amplification or increased mRNA levels) and/or by increased enzymatic activity downstream of hyperactive receptor tyrosine kinases, SRC, chemokine receptors, oxidative stress, assembly of activating protein complexes and inactivation of negative regulatory proteins.
3. Disruption of cell polarity occurs early during tumorigenesis. Activation of ABL kinases results in dramatic inversion of epithelial apical–basal polarity by disrupting β1 integrin signalling and laminin assembly. Thus, activated ABL kinases may regulate early steps of tumour initiation.
4. ABL kinases regulate the function of invadopodia, actin-rich structures that remodel the extracellular matrix during cancer cell invasion. ABL kinases are required for cancer cell invasion by regulating invadopodia components and the expression of genes that promote invasion and metastasis.
5. ABL1 and ABL2 regulate overlapping and distinct cellular processes in various cell types and may differentially contribute to tumour progression. Future studies are required to evaluate unique roles for ABL kinases not only in selected solid tumours but also in cells in the tumour microenvironment.
6. Treatment of BCR–ABL1-positive leukaemias with imatinib has emerged as the best example of the successful use of tyrosine kinase inhibitor (TKI)-targeted therapy. However, use of imatinib and related drugs is inadequate for the treatment of unselected solid tumours. The identification of new allosteric inhibitors with greater specificity against ABL kinases will allow for the evaluation of the contribution of ABL kinases for the treatment of solid tumours with hyperactive ABL kinases.
7. ABL kinases are activated during acquired resistance to chemotherapy, and ABL1 inhibition can sensitize cancer cells to cytotoxic chemotherapies and targeted TKI therapies.

要点翻译：

1. ABL1最初于30多年前被发现，作为艾贝尔森鼠白血病病毒中的癌基因，随后被鉴定为与人类白血病染色体易位相关的癌基因。近年来，在实体肿瘤中检测到ABL1和ABL2的激活。
2. 实体肿瘤中ABL激酶的激活机制包括表达增强（基因扩增或mRNA水平升高）和/或酶活性增加，后者源于过度活化的受体酪氨酸激酶、SRC家族、趋化因子受体、氧化应激、激活型蛋白复合物的组装以及负调控蛋白的失活。
3. 细胞极性破坏是肿瘤发生过程中的早期事件。ABL激酶的激活通过破坏β1整合素信号传导和层粘连蛋白组装，导致上皮细胞顶基极性的显著逆转。因此，激活的ABL激酶可能调控肿瘤起始的早期步骤。
4. ABL激酶调控侵袭伪足的功能——这些富含肌动蛋白的结构在癌细胞侵袭过程中重塑细胞外基质。通过调节侵袭伪足组分及促进侵袭转移基因的表达，ABL激酶对癌细胞侵袭至关重要。
5. ABL1和ABL2在不同细胞类型中调控既有重叠又具特异性的细胞过程，可能以不同方式促进肿瘤进展。未来研究需评估ABL激酶不仅在特定实体肿瘤中，同时在肿瘤微环境细胞中的独特作用。
6. 伊马替尼治疗BCR-ABL1阳性白血病已成为酪氨酸激酶抑制剂靶向治疗成功应用的最佳范例。然而，伊马替尼及相关药物对于未经筛选的实体肿瘤治疗效果有限。针对ABL激酶具有更高特异性的新型变构抑制剂的发现，将有助于评估ABL激酶在治疗ABL过度活化型实体肿瘤中的价值。
7. ABL激酶在化疗获得性耐药过程中被激活，抑制ABL1可增强癌细胞对细胞毒性化疗和靶向TKI治疗的敏感性。

英文摘要：

The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration and invasion. ABL1 was first identified as an oncogene required for the development of leukaemias initiated by retroviruses or chromosome translocations. The demonstration that small-molecule ABL kinase inhibitors could effectively treat chronic myeloid leukaemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumours. Enhanced ABL expression and activation in some solid tumours, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may be useful for treating selected solid tumours.

摘要翻译： 

Abelson（ABL）非受体酪氨酸激酶家族成员ABL1和ABL2，将多种胞外信号传递至调控细胞增殖、存活、迁移与侵袭的蛋白网络。ABL1最初被确认为逆转录病毒或染色体易位诱发白血病所必需的癌基因。小分子ABL激酶抑制剂可有效治疗慢性髓系白血病的发现，开启了靶向肿瘤治疗时代。最新研究揭示ABL激酶在实体瘤中亦发挥作用：部分实体瘤中ABL表达与活性升高，且激活的ABL激酶可改变细胞极性、促进侵袭和生长，提示靶向这些激酶的药物或可用于治疗特定实体瘤。

原文链接：

Role of ABL family kinases in cancer: from leukaemia to solid tumours