Topoisomerase levels determine chemotherapy response in vitro and in vivo

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. Proc Natl Acad Sci U S A, 105 (25). pp. 9053-9058.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18574145
DOI: 10.1073/pnas.0803513105

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.

Item Type: Paper
Uncontrolled Keywords: Chk2 doxorubicin RNAi screen Top1 Top2A
Subjects: therapies
therapies > cancer drugs - see diseases-cancer-drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
diseases & disorders > cancer > cancer types > lymphoma
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Hannon lab
CSHL labs > Lowe lab
CSHL labs > McCombie lab
Watson School > Publications
Depositing User: Tom Adams
Date Deposited: 26 Aug 2011 13:18
Last Modified: 08 Nov 2017 21:34
PMCID: PMC2435590
Related URLs:
URI: http://repository.cshl.edu/id/eprint/7696

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