Casting a NETwork instead of shooting magic bullets.
Casting a NETwork instead of shooting magic bullets.
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建立网络而不是发射魔法子弹。
DOI：
10.1080/15384101.2016.1216926
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Abraham SA
中科院分区：
文献类型：
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作者：
Abraham SA
长期建立的概念是当前癌症治疗发展的基础，重点是针对癌细胞不同且独特的特定分子缺陷；目标是在不伤害周围正常组织的情况下特异性地“射杀”恶性肿瘤。然而，在过去的几年里，人们提出了一个问题，即遵循这一思想的研究努力是否在开发治疗性疗法方面取得了真正的成功，而不是在延长诊断后的预期寿命方面取得了成功。甲磺酸伊马替尼（imatinib mesylate， IM）是一种酪氨酸激酶抑制剂（TKI），是治疗慢性髓性白血病（CML）最成功的合理设计的疗法之一。伊马替尼靶向CML的病原体Bcr-Abl，并导致显著的临床反应，使CML和IM治疗成为单靶点治疗的最佳范例和理由。尽管患者生存率有所提高，但我们和其他人已经证明TKIs不会杀死负责疾病起始和维持的白血病起始细胞（LIC）。接受治疗的患者面临产生耐药性的风险，大多数患者必须无限期服用tki，并伴有相关的短期和长期副作用、依从性问题和费用。在BCR-ABL小鼠模型中实施各种激酶抑制剂、BCR-ABL敲低和移植试验的研究表明，CML LIC的生存不依赖于BCR-ABL激酶活性，这使我们得出结论，CML LIC必须通过其他信号通路维持。我们假设，系统生物学方法识别高度连接的节点，而不是单个蛋白质边缘，可能提供对CML生物学更深入的了解，重要的是产生比单一靶标方法更基本的合成致死性。通过使用网络分析分析来自干细胞祖细胞的CML蛋白质组学特征，我们发现大多数不受调控的蛋白质不仅与p53和c-Myc相连，而且重要的是主要受p53和c-Myc调控（图1）
Long established concepts underlying the current development of cancer therapies focus on targeting specific molecular defects that are different and unique to cancer cells; the goal being to specifically ‘shoot and kill’the malignancy without harming the surrounding normal tissue. However in the last several years, concerns have been raised that question whether research efforts following this ideology have been truly successful in developing curative therapies versus treatments that extend life expectancy post diagnosis. 1Imatinib mesylate (IM), a tyrosine kinase inhibitor (TKI), represents one of the most successful rationally-designed therapeutics for the treatment of Chronic Myeloid Leukemia (CML). Imatinib targets Bcr-Abl, the causative agent of CML and has led to dramatic clinical responses allowing CML and IM therapy to exemplify the best paradigm and justification for single targetbased therapy. Despite the improvements in patient survival, we and others have demonstrated that TKIs do not kill the leukemia initiating cells (LIC) that are responsible for disease initiation and maintenance. Treated patients face the risk of developing drug resistance and most must take TKIs indefinitely with associated short and long term side effects, compliance issues and costs. 2 Studies implementing various kinase inhibitors, BCR-ABL knockdown and transplantation assays in a BCR-ABL mouse model suggest that CML LIC are independent of BCR-ABL kinase activity for their survival, leading us to conclude that alternative signaling pathways must maintain CML LIC. We hypothesized that a systems biology approach to identify highly connected nodes rather than single protein edges may provide deeper insight into CML biology and importantly engender a more fundamental synthetic lethality than single target approaches. By analyzing the CML proteomic signature from stem progenitor cells using network analyses, we identified that the majority of the deregulated proteins are not only connected to, but importantly dominantly regulated by, p53 and c-Myc (Fig. 1). 3