title: Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.
abstract: Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: Niels F
authors.initials: NF
authors.lastname: Jensen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.affiliation: Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Beck
authors.affiliation: Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Hanáková
authors.affiliation: Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark.
authors.forename: Kirstine C
authors.initials: KC
authors.lastname: Belling
authors.affiliation: Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark.
authors.forename: Khoa N
authors.initials: KN
authors.lastname: Do
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Viuff
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: Sune B
authors.initials: SB
authors.lastname: Nygård
authors.affiliation: Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark.
authors.forename: Ramneek
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Rasmussen
authors.affiliation: University of Southern Denmark, Institute of Clinical Research, Oncology Unit, Odense, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Tarpgaard
authors.affiliation: University of Southern Denmark, Institute of Clinical Research, Pathology Unit, Odense, Denmark.
authors.forename: Tine P
authors.initials: TP
authors.lastname: Hansen
authors.affiliation: Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Budinská
authors.affiliation: University of Southern Denmark, Institute of Clinical Research, Oncology Unit, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: University of Lausanne, University Institute of Pathology, Lausanne, Switzerland.
authors.forename: Fred
authors.initials: F
authors.lastname: Bosman
authors.affiliation: University Hospital Gasthuisberg, Digestive Oncology Unit, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: University Hospital of Geneva, Oncosurgery Unit, Geneva, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Roth
authors.affiliation: SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland; University of Lausanne, Ludwig Center for Cancer Research, Lausanne, Switzerland; University of Lausanne, Oncology Department, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark.
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: Maria U
authors.initials: MU
authors.lastname: Rømer
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark. Electronic address: nbr@sund.ku.dk.
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
authors.forename: José M A
authors.initials: JM
authors.lastname: Moreira
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077146:Irinotecan; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin
keywords: Cell line models; Colorectal cancer; Irinotecan; Oxaliplatin; Resistance