Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology
Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology
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DOI：
10.1016/j.coph.2013.06.004
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发表时间：
2013-08-01
影响因子：
4
通讯作者：
Clarke, Paul A.
中科院分区：
文献类型：
--
作者：
Workman, Paul;Al-Lazikani, Bissan;Clarke, Paul A.
我们对肿瘤发生和癌症进展的遗传和表观遗传机制的详细了解取得了非凡的进展。在新一代测序的支持下，许多新的靶点和途径已被确定，以利用致癌基因和非致癌基因成瘾和合成致死性。激酶抑制剂在可药物癌症基因组中占有重要地位，其中 19 种激酶抑制剂已在肿瘤学领域获得批准。虽然生存收益很有价值，但耐药性已成为主要挑战。癌症的克隆异质性和进化是一个内在的问题，还有反馈环路、激酶转换以及替代靶点和途径的激活。解决耐药性需要使用合理针对性的联合治疗方案。基于持续的多技术分析的适应性治疗周期的应用将是长期治疗成功的关键。
Extraordinary progress has been made in our detailed understanding of the genetic and epigenetic mechanisms responsible for oncogenesis and cancer progression. Empowered by next-generation sequencing, many new targets and pathways have been identified to exploit oncogene and non-oncogene addiction and synthetic lethality. Kinase inhibitors feature strongly in the druggable cancer genome and 19 have been approved in oncology. While survival gains are valuable, drug resistance has emerged as the major challenge. The clonal heterogeneity and evolution of cancers is an intrinsic problem, together with feedback loops, kinase switching and activation of alternative targets and pathways. The solution to drug resistance will require the use of rationally targeted combinational regimens. The application of adaptive treatment cycles based on ongoing multi-technology profiling will be the key to long-term therapeutic success.