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.
authors.affiliation: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Alvin J X
authors.initials: AJ
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: Axel
authors.initials: A
authors.lastname: Walther
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Maik
authors.initials: M
authors.lastname: Kschischo
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011003:Ploidies