Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, Western Australia, Australia.
Telethons Kids Institute, Perth's Children Hospital, The University of Western Australia, Nedlands, Perth, Western Australia, Australia.
Mol Cancer Ther. 2019 Dec;18(12):2480-2489. doi: 10.1158/1535-7163.MCT-19-0273. Epub 2019 Aug 29.
Cancer precision medicine aims to predict the drug likely to yield the best response for a patient. Genomic sequencing of tumors is currently being used to better inform treatment options; however, this approach has had a limited clinical impact due to the paucity of actionable mutations. An alternative to mutation status is the use of gene expression signatures to predict response. Using data from two large-scale studies, The Genomics of Drug Sensitivity of Cancer (GDSC) and The Cancer Therapeutics Response Portal (CTRP), we investigated the relationship between the sensitivity of hundreds of cell lines to hundreds of drugs, and the relative expression levels of the targets these drugs are directed against. For approximately one third of the drugs considered (73/222 in GDSC and 131/360 in CTRP), sensitivity was significantly correlated with the expression of at least one of the known targets. Surprisingly, for 8% of the annotated targets, there was a significant anticorrelation between target expression and sensitivity. For several cases, this corresponded to drugs targeting multiple genes in the same family, with the expression of one target significantly correlated with sensitivity and another significantly anticorrelated suggesting a possible role in resistance. Furthermore, we identified nontarget genes that are significantly correlated or anticorrelated with drug sensitivity, and find literature linking several to sensitization and resistance. Our analyses provide novel and important insights into both potential mechanisms of resistance and relative efficacy of drugs against the same target.
癌症精准医学旨在预测药物对患者最有效的反应。肿瘤的基因组测序目前正被用于更好地告知治疗方案；然而，由于可操作的突变较少，这种方法的临床影响有限。替代突变状态的方法是使用基因表达谱来预测反应。我们利用来自两个大型研究的数据，即癌症药物敏感性基因组学（GDSC）和癌症治疗反应门户（CTRP），研究了数百种细胞系对数百种药物的敏感性与这些药物针对的目标的相对表达水平之间的关系。对于大约三分之一的考虑药物（GDSC 中的 73/222 和 CTRP 中的 131/360），敏感性与至少一个已知靶点的表达显著相关。令人惊讶的是，对于 8%的注释靶点，靶点表达与敏感性之间存在显著的负相关。对于几种情况，这对应于靶向同一家族多个基因的药物，一个靶点的表达与敏感性显著相关，而另一个靶点的表达则显著负相关，这表明其可能在耐药性中发挥作用。此外，我们还鉴定了与药物敏感性显著相关或负相关的非靶点基因，并发现文献将几个基因与增敏和耐药联系起来。我们的分析为耐药的潜在机制和同一靶标药物的相对疗效提供了新的重要见解。
