Lippard Paper, "A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress" Published in Nature Medicine

Danielle Randall
February 28, 2017

A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress

Peter M Bruno, Yunpeng Liu, Ga Young Park, Junko Murai, Catherine E Koch, Timothy J Eisen, Justin R Pritchard, Yves Pommier, Stephen J Lippard & Michael T Hemann

Nature Medicine (2017)

doi:10.1038/nm.4291

Published online 27 February 2017

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.

Research in Professor Lippard's laboratory involves bioinorganic chemistry. The core activities include both structural and mechanistic studies of macromolecules as well as synthetic inorganic chemistry. The focus is on the synthesis, reactions, physical and structural properties of metal complexes as models for the active sites of metalloproteins and as anti-cancer drugs. Also included is extensive structural and mechanistic work on the natural systems themselves. A program in metalloneurochemistry is also in place.