Chromosomal Instability Confers Intrinsic Multidrug Resistance

Publication: Research - peer-reviewJournal article – Annual report year: 2011

  • Author: Lee, Alvin J. X.

    Cancer Research UK London Research Institute, Translational Cancer Therapeutics Laboratory

  • Author: Endesfelder, David

    Cancer Research UK London Research Institute, Translational Cancer Therapeutics Laboratory

  • Author: Rowan, Andrew J.

    Cancer Research UK London Research Institute, Translational Cancer Therapeutics Laboratory

  • Author: Walther, Axel

    The Wellcome Trust Centre for Human Genetics, Oxford, Molecular and Population Genetics

  • Author: Birkbak, Nicolai Juul

    Department of Systems Biology, Technical University of Denmark, Kemitorvet, 2800, Lyngby, Denmark

  • Author: Futreal, P. Andrew

    Wellcome Trust Sanger Institute, Cambridge, Cancer Genome Project

  • Author: Downward, Julian

    Cancer Research UK London Research Institute, Signal Transduction Laboratory

  • Author: Szallasi, Zoltan Imre

    Department of Systems Biology, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Tomlinson, Ian P. M.

    The Wellcome Trust Centre for Human Genetics, Oxford, Molecular and Population Genetics

  • Author: Howell, Michael

    Cancer Research UK London Research Institute, High Throughput Screening Laboratory

  • Author: Kschischo, Maik

    University of Applied Sciences, Mathematics and Techniques, Germany

  • Author: Swanton, Charles

    Cancer Research UK London Research Institute, London, Translational Cancer Therapeutics Laboratory

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Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN+) or diploid/near-diploid (CIN-), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN+ cell lines displayed significant intrinsic multidrug resistance compared with CIN- cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN+ displayed multidrug resistance relative to their CIN- parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression-free or disease-free survival relative to patients with CIN- disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity. Cancer Res; 71(5); 1858-70. (c) 2011 AACR.
Original languageEnglish
JournalCancer Research
Publication date2011
Volume71
Journal number5
Pages1858-1870
ISSN0008-5472
DOIs
StatePublished

Bibliographical note

Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

CitationsWeb of Science® Times Cited: 57
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