Systematic identification of genomic markers of drug sensitivity in cancer cells

摘要

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines-which represent much of the tissue-type and genetic diversity of human cancers-with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Swing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poIy(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.%癌细胞系被普遍用作潜伏期（临床前期）模型，来获得有关患病机制和治疗方法的信息。本期Nature上两篇文论介绍了对人类癌细胞系所做的大规模基因和药理定性工作。两个研究小组利用不同平台和分析方法定性了数百个细胞系。他们的结果是互补性的，证实了很多人类细胞系能够捕捉到它们各自癌症的基因组多样性。他们最初获得的发现包括，识别出了有关药物敏感性和抗药性的几个潜在标记。例如，Garnett等人报告了在EWS-FLI1基因转位（常见于Ewing's肉瘤）和对PARP抑制因子（它们是目前用于其他癌症类型的临床试验的一类药物）的敏感性之间所存在的一种联系。Barretina等人报告了在SLFN11表达与对局部异构酶抑制因子的敏感性之间所存在的一种联系。本期封面所示为正在分裂的纤维肉瘤细胞。