TY - JOUR
T1 - Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance
AU - Jensen, Niels F.
AU - Stenvang, Jan
AU - Beck, Mette Kristina
AU - Hanáková, Barbora
AU - Belling, Kirstine C.
AU - Nguyen Do, Khoa
AU - Viuff, Birgitte
AU - Nygård, Sune B.
AU - Gupta, Ramneek
AU - Rasmussen, Mads H.
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 L.
AU - Rømer, Maria U.
AU - Brünner, Nils
AU - Moreira, José M.A.
PY - 2015
Y1 - 2015
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.
KW - CR - complete response
KW - CRC - colorectal cancer
KW - ECM - extracellular matrix
KW - EMT - epithelial–mesenchymal transition
KW - FC - fold-change
KW - 5FU - 5-fluorouracil
KW - OS - overall survival
KW - PR - partial response
KW - RFS - relapse free survival
KW - RR - relative resistance
KW - MSI - microsatellite instability
KW - MSS - microsatellite stable
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 -
