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The complex landscape of non-coding RNAs in olaparib response and resistance
Fatemeh Tahamipour1, Maryam Ghasemi1, Akram Ghahghaei-Nezamabadi2
1Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Abstract:
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.
Insights
Non-coding RNAs (ncRNAs) play a dual role in cancer treatment with poly(ADP-ribose) polymerase inhibitors (PARPi), like olaparib. Understanding these ncRNAs may help overcome resistance and improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Poly(ADP-ribose) polymerase inhibitors (PARPi) have advanced cancer therapy for homologous recombination repair (HRR) deficient tumors, particularly those with BRCA1/2 mutations.
- Clinical use of PARPi, like olaparib, is frequently hindered by acquired or de novo resistance.
- Non-coding RNAs (ncRNAs) are increasingly recognized as key regulators of cellular responses to PARPi therapy.
Purpose of the Study:
- To review the current understanding of ncRNAs' multifaceted roles in modulating sensitivity and resistance to olaparib.
- To explore the mechanisms by which ncRNAs influence HRR pathway genes and alternative signaling cascades.
- To discuss the impact of olaparib treatment on ncRNA expression profiles and potential feedback loops.
Main Methods:
- Literature review synthesizing findings on ncRNAs in olaparib therapy across various cancers.
- Analysis of mechanisms involving ncRNAs in regulating HRR genes (BRCA1, BRCA2, RAD51) and signaling pathways (Wnt/β-catenin, STING).
- Examination of how olaparib treatment alters ncRNA expression.
Main Results:
- ncRNAs can either enhance sensitivity or confer resistance to olaparib by regulating HRR genes and related pathways.
- Olaparib treatment can induce dynamic changes in ncRNA expression, potentially creating feedback loops.
- These ncRNA-mediated effects are observed in diverse cancers, including ovarian, breast, prostate, and hepatocellular carcinoma.
Conclusions:
- ncRNAs represent critical regulators in the context of olaparib therapy, influencing both sensitivity and resistance.
- ncRNAs hold significant potential as predictive biomarkers for PARPi efficacy.
- Targeting ncRNAs may offer novel therapeutic strategies to overcome PARPi resistance and improve cancer treatment outcomes.
