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Mol Oncol. 2015 Jun;9(6):1169-85. doi: 10.1016/j.molonc.2015.02.008. Epub 2015 Feb 24.

Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

Author information

1
University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
2
Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark.
3
Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic.
4
Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark.
5
University of Southern Denmark, Institute of Clinical Research, Oncology Unit, Odense, Denmark.
6
University of Southern Denmark, Institute of Clinical Research, Pathology Unit, Odense, Denmark.
7
University of Lausanne, University Institute of Pathology, Lausanne, Switzerland.
8
University Hospital Gasthuisberg, Digestive Oncology Unit, Leuven, Belgium.
9
University Hospital of Geneva, Oncosurgery Unit, Geneva, Switzerland.
10
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.
11
University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark. Electronic address: nbr@sund.ku.dk.

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.

KEYWORDS:

Cell line models; Colorectal cancer; Irinotecan; Oxaliplatin; Resistance

PMID:
25759163
PMCID:
PMC5528766
DOI:
10.1016/j.molonc.2015.02.008
[Indexed for MEDLINE]
Free PMC Article
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