Skin Biopsies and DNA Analysis in Patients Receiving Irinotecan or Gemcitabine For Advanced Solid Tumors
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Pancreatic Cancer,Breast Neoplasms,Pancreatic Neoplasms,Breast Cancer
PROVIDER: 2032141 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Purpose: Gemcitabine is most commonly used for pancreatic cancer (PC). However, the molecular features and mechanisms of the frequently occurred resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. Experimental Design: In present study, we established 66 patient-derived xenografts (PDXs) based on clinical PC specimens and treated them with gemcitabine. We generated multi-omics data (including whole exome-seq, RNA-seq, miRNA-seq and DNA methylation array) of 15 drug sensitive and 13 resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and required resistance. Then, shRNA-based high-content screening was implemented to validate the function of the de-regulated genes. Results: The comprehensive multi-omics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in PC cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of PC patients and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, HIF-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. Conclusions: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provide potential therapy targets for overcoming gemcitabine resistance.
2021-02-09 | GSE165687 | GEO
Project description:Purpose: Gemcitabine is most commonly used for pancreatic cancer (PC). However, the molecular features and mechanisms of the frequently occurred resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. Experimental Design: In present study, we established 66 patient-derived xenografts (PDXs) based on clinical PC specimens and treated them with gemcitabine. We generated multi-omics data (including whole exome-seq, RNA-seq, miRNA-seq and DNA methylation array) of 15 drug sensitive and 13 resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and required resistance. Then, shRNA-based high-content screening was implemented to validate the function of the de-regulated genes. Results: The comprehensive multi-omics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in PC cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of PC patients and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, HIF-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. Conclusions: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provide potential therapy targets for overcoming gemcitabine resistance.
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2024-09-23 | GSE247163 | GEO
Project description:To investigate the transcriptional alterations that occur during the development of gemcitabine resistance in pancreatic cancer cells, we established gemcitabine-resistant SW1990 cells, referred to as SW1990R. We then employed RNA-seq to explore the transcriptome changes between the gemcitabine-resistant cells and their parental counterparts.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with limited therapeutic options, and gemcitabine insensitivity remains a major challenge. N6-methyladenosine (m6A) is a prevalent nucleotide modification in mRNA that has been linked to various biological processes in human diseases, yet its role in drug sensitivity of cancer remains largely unknown. Herein, by detecting the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified the key role of hyper-m6A modification of the master G0/G1 regulator Fizzy and Cell Division Cycle 20 Related 1 (FZR1) in regulating gemcitabine sensitivity. Targeting m6A modification of FZR1 improves the gemcitabine treatment response of gemcitabine-insensitive PDAC cells in vitro and in vivo. Mechanistically, Gem Nuclear Organelle Associated Protein 5 (GEMIN5) was identified as a novel m6A mediator that specifically binds to m6A-modified FZR1 and recruits the eIF3 translation initiation complex to accelerate FZR1 translation. Upregulation of FZR1 maintains the G0/G1 quiescent state and impairs gemcitabine sensitivity of PDAC cells. Further clinical analysis showed that both high levels of FZR1 m6A modification and FZR1 protein indicated a poor response to gemcitabine. These findings unveil the critical function for m6A modification in regulating gemcitabine sensitivity in PDAC and identify the m6A-FZR1 axis as a potential target to enhance gemcitabine response.
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