A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress
Author(s)Murai, Junko; Pommier, Yves; Hemann, Michael T; Bruno, Peter Michael; Liu, Yunpeng; Park, Ga Young; Koch, Catherine E.; Eisen, Timothy; Pritchard, Justin Robert; Lippard, Stephen J.; Hemann, Michael; ... Show more Show less
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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.
DepartmentInstitute for Medical Engineering and Science; David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry
Bruno, Peter M, Yunpeng Liu, Ga Young Park, Junko Murai, Catherine E Koch, Timothy J Eisen, Justin R Pritchard, Yves Pommier, Stephen J Lippard, and Michael T Hemann. “A Subset of Platinum-Containing Chemotherapeutic Agents Kills Cells by Inducing Ribosome Biogenesis Stress.” Nature Medicine 23, no. 4 (February 27, 2017): 461–471.
Author's final manuscript