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.

• MeSH
• Albumins pharmacology   MeSH
• Deoxycytidine analogs & derivatives   pharmacology   MeSH
• Carcinoma, Pancreatic Ductal drug therapy   genetics   MeSH
• Gemcitabine 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
• Names of Substances
• 130-nm albumin-bound paclitaxel MeSH Browser
• Albumins MeSH
• Deoxycytidine MeSH
• Gemcitabine MeSH
• KRAS protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Paclitaxel MeSH
• Bridged-Ring Compounds MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• taxane MeSH Browser
• Taxoids MeSH

INTRODUCTION: Ovarian cancer (OC) represents a serious disease with high mortality and lack of efficient predictive and prognostic biomarkers. ATP-binding cassette (ABC) proteins constitute a large family dedicated to active transmembrane transport including transport of xenobiotics. MATERIALS AND METHODS: mRNA level was measured by quantitative RT-PCR in tumor tissues from OC patients. Bioinformatics analyses were applied to two gene expression datasets (60 primary tumors and 29 peritoneal metastases). Two different approaches of expression data normalization were applied in parallel, and their results were compared. Data from publically available cancer datasets were checked to further validate our conclusions. RESULTS: The results showed significant connections between ABC gene expression profiles and time to progression (TTP), chemotherapy resistance, and metastatic progression in OC. Two consensus ABC gene profiles with clinical meaning were documented. (a) Downregulation of ABCC4, ABCC10, ABCD3, ABCE1, ABCF1, ABCF2, and ABCF3 was connected with the best sensitivity to chemotherapy and TTP. (b) Oppositely, downregulation of ABCB11 and upregulation of ABCB1 and ABCG2 were connected with the worst sensitivity to chemotherapy and TTP. Results from publicly available online databases supported our conclusions. CONCLUSION: This study stressed the connection between two well-documented ABC genes and clinicopathological features-ABCB1 and ABCG2. Moreover, we showed a comparable connection also for several other ABC genes-ABCB11, ABCC4, ABCC10, ABCD3, ABCE1, ABCF1, ABCF2, and ABCF3. Our results add new clinically relevant information to this oncology field and can stimulate further exploration.

• Keywords
• ABC transporters, bioinformatics, ovarian cancer, resistance, signatures,
• MeSH
• ATP-Binding Cassette Transporters genetics   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Humans MeSH
• RNA, Messenger genetics   MeSH
• Ovarian Neoplasms genetics   pathology   MeSH
• Peritoneal Neoplasms genetics   secondary   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Transcriptome MeSH
• Computational Biology MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ATP-Binding Cassette Transporters MeSH
• RNA, Messenger MeSH