Mapping the Pathways of Resistance to Targeted Therapies.
Mapping the Pathways of Resistance to Targeted Therapies.
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DOI：
10.1158/0008-5472.can-15-1248
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发表时间：
2015-10-15
期刊：
影响因子：
11.2
通讯作者：
Wood KC
中科院分区：
文献类型：
--
作者：
Wood KC
耐药性实质上限制了对靶向抗癌疗法的临床应答的深度和持续时间。通过使用互补的实验方法，研究人员发现，癌细胞可以通过由特定的遗传、表观遗传或微环境改变驱动的适应或选择来实现耐药性。最终，这些不同的改变通常会导致信号通路的激活，当被选择时，使癌细胞能够在药物治疗中存活。最近开发的方法使得能够直接和可扩展地识别能够在特定背景下驱动抗性的信号传导途径。使用这些方法，对临床批准的药物的耐药性的新途径已经被鉴定和验证。通过将系统性耐药途径作图方法与揭示特异性耐药途径的生物标志物和阻断这些途径的药理学方法的研究相结合，可能合理地构建药物组合，从而在患者中产生更持久和持久的反应。
Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacological approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients.