Identifying transcriptomic mechanisms of gemcitabine resistance pathways in pancreatic cancer.

By October 19, 2016April 23rd, 2021Publications

Although pancreatic cancer is increasing in incidence, therapeutic options remain limited. Treatment with gemcitabine or a gemcitabine combination therapy is most common, although current combination therapies are challenged by toxicity. The urgent unmet clinical need for promising novel combination therapies to enhance the efficacy of gemcitabine is suggested by the alarmingly high 5 year mortality rate. We studied gene expression data from 3 pancreatic cancer cell line datasets (Klijn et al, Collisson et al, and CCLE) to query druggable genes and pathways which mastermind gemcitabine resistance or encourage gemcitabine sensitivity. First we processed data and removed low quality samples, then utilized a t-test to pinpoint genes differentially expressed (DE) between cell lines that are sensitive vs resistant to gemcitabine as dictated by Collisson et al’s IC50 values.The overlap of DE genes between all three studies revealed 83 genes upregulated and 48 genes downregulated in gemcitabine resistant cell lines. Specific genes of interest changing include upregulation of apoptosis suppressor TMBIM6 (p<0.003) and pro-survival gene IL20RA (p<0.003) in resistant cell lines. Enrichment of genes upregulated in resistant cell lines includes GEO Kinase perturbation ERBB3 (p.adj=3.28E-08) and GO cyclin-dependent protein serine/threonine kinase regulator activity (p.adj=0.038). GSEAP was conducted in each dataset separately, and top shared significant pathway results include upregulation of KEGG drug metabolism cytochrome P450 (p.adj<0.0003) as well as Retinol metabolism (p.adj<0.0004). Drugs which downregulate these genes and pathways may enhance the effect of gemcitabine. Enrichment of genes upregulated in sensitive cell lines includes GEO Kinase Perturbation ALK (p.adj=1.16E-05) and IRAK4 (4.93E-06), as well as PPI Hub protein PRKACA. Drugs which enhance these kinases and hub proteins may increase effectiveness of gemcitabine.Ongoing work includes analysis to pinpoint drugs which may appropriately enhance or suppress above mentioned master regulators of resistance. Functional genomic studies are underway to validate key targets. By leveraging publicly available data to detailing a consistent gene set which separates gemcitabine sensitive from resistant pancreatic cancer cell lines, we have characterized numerous potential driver candidates and pathways which could be the key to a novel gemcitabine combination.