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Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

The Pharmacogenomics Journal volume 9, pages 90–102 (2009)Cite this article

Abstract

AZD1152 is a highly selective Aurora B kinase inhibitor currently undergoing Phase I and II clinical evaluation in patients with acute myelogenous leukemia and advanced solid malignancies. We have established two AZD1152-resistant cell lines from SW620 colon and MiaPaCa pancreatic carcinoma lines, which are >100-fold resistant to the active metabolite of AZD1152, AZD1152 HQPA and interestingly, cross-resistant to the pan-Aurora kinase inhibitor, VX-680/MK0457. Using whole-genome microarray analysis and comparative genomic hybridization, we were able to identify MDR1 and BCRP as the causative genes that underlie AZD1152 HQPA-resistance in these models. Furthermore, the upregulation of either of these genes is sufficient to render in vivo tumor growth insensitive to AZD1152. Finally, the upregulation of MDR1 or BCRP is predictive of tumor cell sensitivity to this agent, both in vitro and in vivo. The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy.

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Acknowledgements

We thank Steven K Davidsen for critical review of the article and Daniel A Bow for helpful discussions. We thank Zhiquin Ji for the chemical synthesis of MLN8054 and AZD1152 and Douglas H Steinman for synthesizing VX-680. We would like to thank Kenneth B. Idler for DNA sequencing of the Aurora B gene.

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Authors and Affiliations

  1. Cancer Biology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    J Guo, P Tapang, J P Palma, L E Rodriguez, A Niquette, J Li, J J Bouska, G Wang, D Semizarov, D H Albert, C K Donawho, K B Glaser & O J Shah

  2. Gene Expression and Analysis, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    M G Anderson

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Correspondence to O J Shah.

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Guo, J., Anderson, M., Tapang, P. et al. Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152. Pharmacogenomics J 9, 90–102 (2009). https://doi.org/10.1038/tpj.2008.20

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