title: A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress.
abstract: 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.
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Peter M
authors.identifier: http://orcid.org/0000-0003-3383-0118
authors.initials: PM
authors.lastname: Bruno
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Ga Young
authors.initials: GY
authors.lastname: Park
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Koch
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Eisen
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Pritchard
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms; D001678:Organelle Biogenesis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010617:Phenanthridines / Q000494:pharmacology; D017671:Platinum Compounds / Q000494:pharmacology; D025341:Principal Component Analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000187:drug effects*; D013312:Stress, Physiological; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010617:Phenanthridines; D017671:Platinum Compounds; D034741:RNA, Small Interfering; C587603:phenanthriplatin; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin