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KRAS pathway expression changes in pancreatic cancer models by conventional and experimental taxanes
M. Oliverius, D. Flasarova, B. Mohelnikova-Duchonova, M. Ehrlichova, V. Hlavac, M. Kocik, O. Strouhal, P. Dvorak, I. Ojima, P. Soucek,
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV16-28375A
MZ0
CEP Register
Digital library NLK
Full text - Article
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
Medline Complete (EBSCOhost)
from 1996-01-01 to 1 year ago
PubMed
31375828
DOI
10.1093/mutage/gez021
Knihovny.cz E-resources
- MeSH
- Albumins pharmacology MeSH
- Deoxycytidine analogs & derivatives pharmacology MeSH
- Carcinoma, Pancreatic Ductal drug therapy genetics MeSH
- Humans MeSH
- Mice, Nude MeSH
- Mice MeSH
- Biomarkers, Tumor genetics MeSH
- Cell Line, Tumor MeSH
- Pancreatic Neoplasms drug therapy genetics MeSH
- Paclitaxel pharmacology MeSH
- Bridged-Ring Compounds pharmacology MeSH
- Cell Proliferation drug effects genetics MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Proto-Oncogene Proteins p21(ras) genetics MeSH
- Signal Transduction drug effects genetics MeSH
- Taxoids pharmacology MeSH
- Transcriptome drug effects genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Transplantation Center Institute of Clinical and Experimental Medicine Prague Czech Republic
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- $a Oliverius, M $u Department of Surgery, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic. Transplantation Center, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
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- $a The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.
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