Topoisomerase levels determine chemotherapy response in vitro and in vivo

Darren J. Burgess, Jason Doles, Lars Zender, Wen Xue, Beicong Ma, W. Richard McCombie, Gregory J. Hannon, Scott W. Lowe, Michael T. Hemann

Research output: Contribution to journalArticle

210 Scopus citations

Abstract

Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic.

Original languageEnglish (US)
Pages (from-to)9053-9058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number26
DOIs
StatePublished - Jul 1 2008

Keywords

  • Chk2
  • Doxorubicin
  • RNAi screen
  • Top1
  • Top2A

ASJC Scopus subject areas

  • General

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    Burgess, D. J., Doles, J., Zender, L., Xue, W., Ma, B., McCombie, W. R., Hannon, G. J., Lowe, S. W., & Hemann, M. T. (2008). Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 105(26), 9053-9058. https://doi.org/10.1073/pnas.0803513105