Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a G-quadruplex-binding small molecule

Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signalling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the quadruplex-binding compound CM03. This has been designed by computer modelling, is a potent inhibitor of cell growth in PDAC cell lines and has anti-cancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyse for the first time the effects of a quadruplex-binding small molecule on gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC, and may be applicable to other currently hard-to-treat cancers. 12 libraries for MIA PACA-2 cell line (6 and 24 hrs treatment with CM03 drug plus untreated control); 12 libraries for PANC-1 cell line (6 and 24 hrs treatment with CM03 drug plus untreated control); 28 libraries for MIA PACA-2 cell line (6 and 24 hrs treatment at 3 different concentrations with gemcitabine drug plus untreated control); 52 libraries for PANC-1 cell line (6 and 24 hrs treatment at 5 different concentrations with gemcitabine drug plus untreated control). Each condition has 3 or 4 biological replicates. See details below for concentration, treatment and replicates.