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Chromosomal Instability Confers Intrinsic Multidrug Resistance

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Chromosomal Instability Confers Intrinsic Multidrug Resistance Cancer Therapeutics, Targets, and Chemical Biology Research Chromosomal Instability Confers Intrinsic Multidrug Resistance Alvin J.X. Lee1, David Endesfelder1,4, Andrew J. Rowan1, Axel Walther5,6, Nicolai J. Birkbak7, P. Andrew Futreal8, Julian Downward2, Zoltan Szallasi7,9, Ian P.M. Tomlinson5, Michael Howell3, Maik Kschischo4, and Charles Swanton1,6 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 þ colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN ) or diploid/near- À diploid (CIN ), and treated them individually with a library of kinase inhibitors targeting components of signal þ transduction, cell cycle, and transmembrane receptor signaling pathways. CIN cell lines displayed significant À 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 þ À line models of CIN displayed multidrug resistance relative to their CIN parental cancer cell line derivatives. In þ a meta-analysis of CRC outcome following cytotoxic treatment, CIN predicted worse progression-free or À 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. Ó2011 AACR. Introduction instability (CIN), resulting in ongoing numerical and struc- tural chromosomal aberrations in cancer cells, leading to Colorectal cancer (CRC) is associated with at least 2 intratumoral heterogeneity (2, 3). The less common pattern distinct patterns of genomic instability (1). The more com- is microsatellite instability (MIN) caused by a deficiency in mon form of genomic instability in CRC is chromosomal the mismatch repair apparatus. Because of the accumulation of replication errors, MIN results in length variation of þ microsatellite sequences in DNA. Most MIN CRC cell lines À 1 are near-diploid (4, 5) and chromosomally stable (CIN ). In Authors' Affiliations: Translational Cancer Therapeutics Laboratory, þ 2Signal Transduction Laboratory, and 3High Throughput Screening contrast, CIN CRC cell lines are aneuploid and display a Laboratory, Cancer Research UK London Research Institute, London, higher frequency of chromosomal missegregation errors United Kingdom; 4University of Applied Sciences, Mathematics and 5 during each mitosis relative to diploid cells (2). In human Techniques, Remagen, Germany; Molecular and Population Genetics, þ The Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; CRC, CIN is widely inferred through the measurement of 6 Royal Marsden Hospital, Department of Medicine, Sutton, United King- tumor DNA ploidy (6); normal diploid cells are defined with dom; 7Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; 8Cancer Genome Project, Wellcome Trust a DNA index of 1.0 (7) and thus an increase in DNA index Sanger Institute, Cambridge, United Kingdom; and 9Children's Hospital infers polyploidy or aneuploidy. Approximately 25% of À À Informatics Program at the Harvard-MIT Division of Health Sciences and human CRC are both CIN and MIN (6). Technology, Harvard Medical School, Boston, Massachusetts þ Consistent molecular mechanisms responsible for the CIN Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). phenotype and hence means to target this pattern of genome instability in colorectal and other solid tumors remain poorly A.J.X. Lee and D. Endesfelder contributed equally to the work. defined. Putative mechanisms that may contribute to CIN Corresponding Author: Charles Swanton, Translational Cancer Therapeu- ticsLaboratory, Cancer Research UKLondonResearch Institute,44Lincoln's include weakening of the spindle assembly checkpoint (SAC; Inn Fields, London WC2A 3LY, United Kingdom. Phone: 44-20-7269-3463; refs. 8, 9), defective sister chromatid cohesion (10), merotelic Fax 44-20-7269-3094; E-mail: [email protected] sister chromatid attachments (11), defective cytokinesis (12), doi: 10.1158/0008-5472.CAN-10-3604 centrosome amplification (13), and chromosome breakage– Ó2011 American Association for Cancer Research. fusion–bridge cycles (14). 1858 Cancer Res; 71(5) March 1, 2011 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. CIN Confers Intrinsic Multidrug Resistance Increasing evidence suggests that CIN is associated with analysis were present within the CLP database, and a total of poor prognosis in solid tumors (6, 15, 16). It has been sug- 20 of the 61 genes resequenced in the project were found to gested that adverse outcome associated with CIN may be have somatic mutations in at least 1 of those 21 cell lines. related to increased tumor cell heterogeneity, driving the Additional information regarding the somatic mutation status ability of tumors to adapt to environmental stresses (17– of APC, CTNNB1, KRAS, MLH1, PIK3CA, and TP53 were 19). Consistent with a hypothesis whereby CIN may enhance obtained from both published (32–35) and internal laboratory þ À tumor adaptation, transient initiation of CIN, following the data. Isogenic HCT116 MAD2 / cell lines (9) and HCT116 À À brief induction of MAD2 expression in activated KRAS- PTTG1 / cell lines (10) were donated courtesy of Drs. initiated mouse lung tumor models, is associated with a high Benezra and Vogelstein, respectively. To generate tetraploid frequency of tumor recurrence following withdrawal of the HCT116 cells, naturally occurring tetraploid cells were iso- KRAS oncogenic stimulus (20). Preclinical studies have shown lated from the parental cell line and single cell sorted using that CIN is associated with the rapid acquisition of multidrug flow cytometry. Clonal FISH was performed with centromere resistance in cell line systems (21) and intrinsic taxane resis- enumeration probes against centromeres on chromosomes 2 tance in vitro and in vivo (22). Recently, we and others have and 15. proposed the existence of a CIN survival phenotype that þ allows CIN tumor cells to tolerate the impact of excessive Calbiochem Kinase Inhibitor Library and 5-FU screen chromosome gains and losses (22–24) that may in turn impact Calbiochem Kinase Inhibitor Libraries I and II (EMD Bios- upon altered drug sensitivity. ciences) containing 160 inhibitors were used. Comprehensive Determining how CIN might impact upon prognosis and data for these inhibitors including references documenting how this pattern of genomic instability might be specifically target inhibition or downstream signaling cascade inactiva- targeted remains an important research area (23, 25). Evi- tion can be found on the manufacturer's Web site (36). dence in lower eukaryotes has shown that aneuploid Sacchar- Cells were plated into 96-well tissue culture microplates at omyces cerevisiae are dependent on increased glucose an initial seeding density of 4,000 cells per well. After 24 hours, utilization and are more sensitive to both heat shock protein cells were treated with the inhibitors at a final concentration of 90 and proteosome inhibitors (26). Polyploid S. cerevisiae are 10 mmol/L per well. This concentration was selected following dependent upon increased expression of genes involved in drug titration test analysis to give an optimal range of mean sister chromatid cohesion and mitotic spindle function (27). relative surviving cells following inhibitor treatment across all Roschke and Kirsch have shown the existence of anticancer cell lines. After 72 hours of treatment, cell viability was assayed compounds that may specifically target karyotypically com- using the Celltiter-Blue Cell Viability Assay (Promega) accord- plex cancer cells (25). These observations indicate that ing to the manufacturer's instructions. The fluorescent readout karyotypic instability may be specifically targeted in eukar- for each inhibitor treated well was normalized to vehicle yotic organisms and suggest that CIN might be an exploitable control wells. For the HCT116 MAD2 isogenic cell lines, a final and targetable phenotype in cancer. inhibitor concentration of 1 mmol/L per well was used to allow To identify distinct therapeutic approaches to limit the for a larger range of surviving cells across all inhibitors. þ growth of CIN tumors relative to diploid cells, we focused on 5-Fluorouracil (5-FU) was used at both 1 and 10 mmol/L for a panel of CRC cell lines that had previously been classified as a treatment length of 72 hours. The 27 CRC cell lines were þ À CIN or CIN and used kinase inhibitor and cytotoxic libraries plated and assayed
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