Gene expression deregulation in ovarian cancer cells with acquired inverse resistance to paclitaxel and cisplatin

Resistance to anti-cancer drugs is the main challenge in oncology. In pre-clinical studies established cancer cell lines are primary tools in deciphering molecular mechanisms of this phenomenon. In this study we proposed a new approach, based on a model of isogenic cancer cell lines with gradually changing resistance. We analyzed trends in gene expression to find out a scaffold of resistance development process. Ovarian cancer cell line A2780 was treated with stepwise increased concentrations of paclitaxel (PTX) to generate a series of drug resistant sublines. To monitor transcriptome changes we submitted them to mRNA-sequencing, followed by identification of differentially expressed genes (DEGs), principal component analysis (PCA) and hierarchical clustering. Functional interactions of proteins, encoded by DEGs, were analyzed by building protein-protein interaction (PPI) networks. We provided a model of human ovarian cancer cell lines with gradually developed resistance to PTX and collateral sensitivity to cisplatin (CDDP) (inverse resistance). In their transcriptomes we identified two groups of DEGs: 1) with fluctuations in expression in the course of resistance acquiring; and 2) with consistently changed expression in each stage of resistance development, constituting a scaffold of the process. In the scaffold PPI network, cell cycle regulator – PLK2; proteins belong to TNF ligand and receptor family as well as ephrin receptor family were found, but proteins linked to osteo- and chondrogenesis and nervous system development turned out to be key players. Our cellular model of drug resistance allowed for keeping track of trends in gene expression and studying this phenomenon as a process of evolution. This approach revealed that abrogation of osteomimic phenotype in ovarian cancer cells may occur during the development of inverse resistance to PTX and CDDP. Overall design: Examination of genome-wide expression profile in series of A2780-derived sublines with gradually increasing resistance to PTX and sensitivity to CDDP. Fourteen samples were analyzed, each one in two replicates. A2780 untreated cells were references samples.