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Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

SUBMITTER: Du J

PROVIDER: S-EPMC7396420 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels.

Du Jiali J Gu Jichun J Li Ji J

Bioscience reports 20200701 7

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug ...[more]

PMID: 32677676

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Project description:Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

Dataset Information

Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels.

Publications

Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels.

Similar Datasets

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