The complex landscape of non-coding RNAs in olaparib response and resistance

Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have revolutionized the treatment of cancers with deficiencies in homologous recombination repair (HRR), most notably those with BRCA1/2 mutations. However, the clinical efficacy of olaparib is often limited by the development of both acquired and de novo resistance. Emerging evidence shows the role of non-coding RNAs, including miRNAs, lncRNAs, and circRNAs, as critical regulators of cellular response to olaparib. This review synthesizes current findings on the dual role of ncRNAs in the context of olaparib therapy. We first discuss ncRNAs that modulate sensitivity or resistance to olaparib, detailing their mechanisms of action, which often involve direct or indirect regulation of key HRR genes like BRCA1, BRCA2, and RAD51, as well as alternative signaling pathways such as Wnt/β-catenin and STING. Subsequently, we explore how olaparib treatment itself can alter the expression profile of ncRNAs, creating a dynamic feedback loop that may influence therapeutic outcome. By consolidating these findings across various cancers, including ovarian, breast, prostate, and hepatocellular carcinoma, this review highlights the potential of ncRNAs as both predictive biomarkers and therapeutic targets to overcome PARPi resistance and enhance patient outcomes.