Bruno Peter M, Liu Yunpeng, Park Ga Young, Murai Junko, Koch Catherine E, Eisen Timothy J, Pritchard Justin R, Pommier Yves, Lippard Stephen J, Hemann Michael T
The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nat Med. 2017 Apr;23(4):461-471. doi: 10.1038/nm.4291. Epub 2017 Feb 27.
Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.
顺铂及其铂类类似物卡铂和奥沙利铂是一些使用最为广泛的癌症化疗药物。虽然顺铂和卡铂主要用于治疗生殖细胞癌、乳腺癌和肺癌，但奥沙利铂几乎专门用于治疗结直肠癌和其他胃肠道癌症。在此，我们采用一种独特的多平台遗传学方法来研究这些临床常用的铂类抗癌药物以及最近研发的顺铂类似物的作用机制。我们发现，与顺铂和卡铂不同，奥沙利铂并非通过DNA损伤反应来杀死细胞。相反，奥沙利铂通过诱导核糖体生物合成应激来杀死细胞。药物作用机制的这种差异解释了奥沙利铂相对于顺铂在临床应用上的不同，并且这可能有助于根据机制为不同的恶性肿瘤合理选择不同的铂类药物。这些数据凸显了一线癌症治疗核心成分的功能多样性，以及基于机制的原理在应用我们现有的抗癌药物 arsenal 中的潜在益处。
