Chromosomal Instability Confers Intrinsic Multidrug Resistance

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

Standard

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.

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

Harvard

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

APA

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

CBE

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. 71(5):1858-1870. Available from: 10.1158/0008-5472.CAN-10-3604

MLA

Vancouver

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. Available from: 10.1158/0008-5472.CAN-10-3604

Author

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, Vol. 71, No. 5, 2011, p. 1858-1870.

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

Bibtex

@article{26be6367a12846ebad9aec703b4b7795,
title = "Chromosomal Instability Confers Intrinsic Multidrug Resistance",
publisher = "American Association for Cancer Research (A A C R)",
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",
volume = "71",
number = "5",
pages = "1858--1870",
journal = "Cancer Research",
issn = "0008-5472",

}

RIS

TY - JOUR

T1 - Chromosomal Instability Confers Intrinsic Multidrug Resistance

A1 - Lee,Alvin J. X.

A1 - Endesfelder,David

A1 - Rowan,Andrew J.

A1 - Walther,Axel

A1 - Birkbak,Nicolai Juul

A1 - Futreal,P. Andrew

A1 - Downward,Julian

A1 - Szallasi,Zoltan Imre

A1 - Tomlinson,Ian P. M.

A1 - Howell,Michael

A1 - Kschischo,Maik

A1 - Swanton,Charles

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

PB - American Association for Cancer Research (A A C R)

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.

UR - http://cancerres.aacrjournals.org/

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

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

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 5

VL - 71

SP - 1858

EP - 1870

ER -