Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.
Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.
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DOI：
10.1126/scitranslmed.aaw8412
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发表时间：
2019-09-11
影响因子：
17.1
通讯作者：
Sheltzer JM
中科院分区：
文献类型：
--
作者：
Lin A;Giuliano CJ;Palladino A;John KM;Abramowicz C;Yuan ML;Sausville EL;Lukow DA;Liu L;Chait AR;Galluzzo ZC;Tucker C;Sheltzer JM
在肿瘤学临床试验中测试的97%的药物适应症对从未提前获得FDA的批准。虽然缺乏疗效和剂量限制性毒性是试验失败的最常见原因，但许多新药遇到这些问题的原因尚不清楚。利用CRISPR/Cas9诱变技术，我们研究了一组处于不同临床试验阶段的抗癌药物和药物靶点。我们发现，与之前主要用RNAi和小分子抑制剂获得的报告相反，这些药物表面上靶向的蛋白质对癌细胞增殖并不是必需的。此外，我们测试的每种药物的功效都不受其假定靶标丢失的影响，这表明这些化合物通过脱靶效应杀死细胞。通过应用基因靶标反卷积策略，我们发现错误表征的抗癌药物OTS964实际上是细胞周期蛋白依赖性激酶CDK11的有效抑制剂，并且多种癌症类型依赖于CDK11的表达。我们建议，在临床前环境中对癌症药物的作用机制进行严格的基因验证，可能会减少在人类患者中测试的无法提供任何临床益处的治疗方法的数量。CRISPR揭示了许多癌症药物靶点对于细胞增殖是必不可少的，并将CDK11鉴定为一种错误表征的药物的靶点。
97% of drug-indication pairs that are tested in clinical trials in oncology never advance to receive FDA approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well-understood. Using CRISPR/Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that – contrary to previous reports obtained predominantly with RNAi and small-molecule inhibitors – the proteins ostensibly targeted by these drugs are non-essential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we discovered that the mischaracterized anti-cancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. CRISPR reveals that many cancer drug targets are dispensable for cell proliferation and identifies CDK11 as the target of one mischaracterized agent.
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影响因子：
9
作者：
Cao J;Lv W;Wang L;Xu J;Yuan P;Huang S;He Z;Hu J
通讯作者：
Hu J
影响因子：
7
作者：
Castillo, Judit;Knol, Jaco C.;Jansen, Bastiaan J. H.
通讯作者：
Jansen, Bastiaan J. H.
影响因子：
50.3
作者：
Canovas, Begona;Igea, Ana;Nebreda, Angel R.
通讯作者：
Nebreda, Angel R.
影响因子：
--
作者：
Alachkar H;Mutonga M;Malnassy G;Park JH;Fulton N;Woods A;Meng L;Kline J;Raca G;Odenike O;Takamatsu N;Miyamoto T;Matsuo Y;Stock W;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
15
作者：
Botham RC;Fan TM;Im I;Borst LB;Dirikolu L;Hergenrother PJ
通讯作者：
Hergenrother PJ