TY - JOUR
T1 - Establishment and characterization of models of chemotherapy resistance in colorectal cancer
T2 - towards a predictive signature of chemoresistance
AU - Jensen, Niels Frank
AU - Stenvang, Jan
AU - Beck, Mette K.
AU - Hanáková, Barbora
AU - Belling, Kirstine Christensen
AU - Do, Khoa N.
AU - Viuff, Birgitte Martine
AU - Nygård, Sune Boris
AU - Gupta, Ramneek
AU - Rasmussen, Mads Heilskov
AU - Tarpgaard, Line S.
AU - Hansen, Tine P.
AU - Budinská, Eva
AU - Pfeiffer, Per
AU - Bosman, Fred
AU - Tejpar, Sabine
AU - Roth, Arnaud
AU - Delorenzi, Mauro
AU - Andersen, Claus Lindbjerg
AU - Rømer, Maria Unni Koefoed
AU - Brünner, Nils
AU - Moreira, José
N1 - Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.molonc.2015.02.008
DO - 10.1016/j.molonc.2015.02.008
M3 - Journal article
C2 - 25759163
SN - 1574-7891
VL - 9
SP - 1169
EP - 1185
JO - Molecular Oncology
JF - Molecular Oncology
IS - 6
ER -
