A subset of platinum-containing chemotherapeutic agents kill cells by inducing ribosome biogenesis stress rather than by engaging a DNA damage response

Cisplatin and its platinum analogues, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. However, although cisplatin and carboplatin are primarily used in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively in 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 analogues. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells via 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 may 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. Corresponding author statement: Michael Hemann (hemann@mit.edu) and Stephen Lippard (lippard@mit.edu). Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Author Contributions P.M.B., Y.L., G.Y.P, T.J.E., J.R.P., D.P.B., Y.P., S.J.L and M.T.H. conceived the idea for the research, designed experiments and interpreted data. P.M.B., Y.L. and C.E.K. performed experiments. P.M.B. and Y.L. performed bioinformatic analyses. J.M. performed DT40 sensitivity profiles. T.J.E. performed polysome gradient profiling. P.M.B., S.J.L. and M.T.H. wrote the paper. Competing Financial Interests Statement The authors declare no competing financial interests. HHS Public Access Author manuscript Nat Med. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: Nat Med. 2017 April ; 23(4): 461–471. doi:10.1038/nm.4291. A uhor M anscript