Identification of novel gene expression patterns and pathways involved in PARP-1 inhibitor resistance.

Abstract

US-FDA has approved PARP-1 inhibitors (Talazoparib, Olaparib, Rucaparib, and Niraparib) as the first line of treatment for many cancer types (e.g., breast, ovarian, pancreatic, and prostate) caused by mutations in breast cancer gene 1 and 2 (BRCA1/2). However, developing resistance to PARP-1 inhibitors is a major concern, which limits therapeutic effectiveness. In the present study, we identified novel gene signatures implicated in developing resistance to Olaparib. Meta-analysis was performed on publicly available RNA-Seq data related to ovarian and breast cancers from the GEO (Gene Expression Omnibus) database. Differential gene expression analysis, gene ontology, KEGG pathway enrichment, and protein-protein interaction (PPI) networking analyses were performed. A total of 139 Common DEGs (Differentially Expressed Genes) were identified, comprising 69 and 70 genes that were upregulated and downregulated respectively. KEGG Pathways "P53 signaling pathway" and "Positive regulation of developmental process(BP)", "endoplasmic reticulum lumen(CC)," and "growth factor binding(MF)", were found to be potentially associated with Olaparib resistance. Five hub genes were identified using PPI networking of which FN1, CCN2, and JUN may play a significant role in the development of Olaparib resistance and could be promising therapeutic and diagnostic biomarkers for dealing with Olaparib resistance in BRCA1/2 mutant breast and ovarian cancer.