Multidrug resistance genes screening of pancreatic ductal adenocarcinoma based on sensitivity profile to chemotherapeutic drugs

Abstract

BackgroundsPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and chemotherapeutic drug resistance is a stumbling block in improving the overall survival of PDAC patients. The nature of specific drug resistant subpopulation within pancreatic ductal adenocarcinoma is believed to be partly attributed to epithelial-mesenchymal transition (EMT) and cell stemness. Various PDAC cell lines show various degrees of resistance to chemotherapeutic agents including gemcitabine (GEM) and 5-fluorouracil (5-FU). In-depth understanding of drug resistance mechanisms and profile heterogeneities could lead to the development of novel and precise therapeutic strategies for addressing the chemo-resistant dilemma in PDAC patients.MethodsCytotoxicity assays were performed by CCK8 in ten common PDAC cell lines including AsPC-1, BxPC-3, CAPAN-1, CFPAC, HPAFII, MIA PaCa-2, PANC-1, Patu-8988, SW1990 and T3M4. RNA-seq data of the ten cell lines were downloaded from Cancer Cell Line Encyclopedia (CCLE) database and subsequently analyzed for differentially expressed genes (DEGs). Based on first-line chemotherapy regimens of PDAC, DEGs between resistant and sensitive cell lines were validated by qRT-PCR. Enriched pathways of differentially expressed genes between the resistant and sensitive cell lines were acquired by Metascape database.ResultsWe found that the top two toxic drugs for PDAC cell lines were paclitaxel (PTX) and GEM. Among the ten PDAC cell lines, SW1990 was the most resistant PDAC cell line with the highest IC50 levels for three drugs, while MIA PaCa-2 and BxPC-3 were the most sensitive PDAC cell lines. Differential expression analysis revealed the highest number of DEGs associated with cisplatin (CIS) sensitivity up to 642 genes, of which 181 genes were upregulated and 461 genes were downregulated in CIS-resistant cell lines. The least number of DEGs are associated with GEM sensitivity, of which 37 genes were highly expressed in GEM-resistant PDAC cell lines and 25 genes were lowly expressed. Enrichment analysis of the DEGs revealed that pathways associated with drug resistance were mainly extracellular matrix and cell–cell junction related pathways.ConclusionsPDAC cell lines showed diverse sensitivities to commonly used chemotherapeutic agents, which was caused by differential gene expression between the resistant and sensitive cell lines. The heterogeneity and its associated genes were enriched in extracellular matrix and cell–cell junction related pathways. Our study first portrayed the sensitivity profile to chemotherapeutic drugs of PDAC, which would benefit the chemoresistance mechanism study by reemphasizing the vital role of extracellular matrix and cell–cell junction related pathways and helping the selection of suitable PDAC cell lines.