Chromosomal Instability Confers Intrinsic Multidrug Resistance

Alvin J. X. Lee, David Endesfelder, Andrew J. Rowan, Axel Walther, Nicolai Juul Birkbak, P. Andrew Futreal, Julian Downward, Zoltan Imre Szallasi, Ian P. M. Tomlinson, Michael Howell, Maik Kschischo, Charles Swanton

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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
    Volume71
    Issue number5
    Pages (from-to)1858-1870
    ISSN0008-5472
    DOIs
    Publication statusPublished - 2011

    Bibliographical note

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

    Cite this

    Lee, A. J. X., Endesfelder, D., Rowan, A. J., Walther, A., Birkbak, N. J., Futreal, P. A., ... Swanton, C. (2011). Chromosomal Instability Confers Intrinsic Multidrug Resistance. Cancer Research, 71(5), 1858-1870. https://doi.org/10.1158/0008-5472.CAN-10-3604
    Lee, Alvin J. X. ; Endesfelder, David ; Rowan, Andrew J. ; Walther, Axel ; Birkbak, Nicolai Juul ; Futreal, P. Andrew ; Downward, Julian ; Szallasi, Zoltan Imre ; Tomlinson, Ian P. M. ; Howell, Michael ; Kschischo, Maik ; Swanton, Charles. / Chromosomal Instability Confers Intrinsic Multidrug Resistance. In: Cancer Research. 2011 ; Vol. 71, No. 5. pp. 1858-1870.
    @article{26be6367a12846ebad9aec703b4b7795,
    title = "Chromosomal Instability Confers Intrinsic Multidrug Resistance",
    abstract = "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.",
    author = "Lee, {Alvin J. X.} and David Endesfelder and Rowan, {Andrew J.} and Axel Walther and Birkbak, {Nicolai Juul} and Futreal, {P. Andrew} and Julian Downward and Szallasi, {Zoltan Imre} and Tomlinson, {Ian P. M.} and Michael Howell and Maik Kschischo and Charles Swanton",
    note = "Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).",
    year = "2011",
    doi = "10.1158/0008-5472.CAN-10-3604",
    language = "English",
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    Lee, AJX, Endesfelder, D, Rowan, AJ, Walther, A, Birkbak, NJ, Futreal, PA, Downward, J, Szallasi, ZI, Tomlinson, IPM, Howell, M, Kschischo, M & Swanton, C 2011, 'Chromosomal Instability Confers Intrinsic Multidrug Resistance', Cancer Research, vol. 71, no. 5, pp. 1858-1870. https://doi.org/10.1158/0008-5472.CAN-10-3604

    Chromosomal Instability Confers Intrinsic Multidrug Resistance. / Lee, Alvin J. X.; Endesfelder, David; Rowan, Andrew J.; Walther, Axel; Birkbak, Nicolai Juul; Futreal, P. Andrew; Downward, Julian; Szallasi, Zoltan Imre; Tomlinson, Ian P. M.; Howell, Michael; Kschischo, Maik; Swanton, Charles.

    In: Cancer Research, Vol. 71, No. 5, 2011, p. 1858-1870.

    Research output: Contribution to journalJournal articleResearchpeer-review

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    T1 - Chromosomal Instability Confers Intrinsic Multidrug Resistance

    AU - Lee, Alvin J. X.

    AU - Endesfelder, David

    AU - Rowan, Andrew J.

    AU - Walther, Axel

    AU - Birkbak, Nicolai Juul

    AU - Futreal, P. Andrew

    AU - Downward, Julian

    AU - Szallasi, Zoltan Imre

    AU - Tomlinson, Ian P. M.

    AU - Howell, Michael

    AU - Kschischo, Maik

    AU - Swanton, Charles

    N1 - Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

    PY - 2011

    Y1 - 2011

    N2 - 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.

    AB - 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.

    U2 - 10.1158/0008-5472.CAN-10-3604

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    Lee AJX, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA et al. Chromosomal Instability Confers Intrinsic Multidrug Resistance. Cancer Research. 2011;71(5):1858-1870. https://doi.org/10.1158/0008-5472.CAN-10-3604