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Published on: June 12, 2018
Identification of miRNA modulators to PARP inhibitor response
Sari Neijenhuis1, Ilirjana Bajrami, Rowan Miller
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.
Abstract:
Based on the principle of synthetic lethality, PARP inhibitors have been shown to be very effective in killing cells deficient in homologous recombination (HR), such as those bearing mutations in BRCA1/2. However, questions regarding their wider use persist and other determinants of responsiveness to PARP inhibitor remain to be fully explored. MicroRNAs (miRNAs) are small non-coding RNAs, which serve as post-transcriptional regulators of gene expression and are involved in a wide variety of cellular processes, including the DNA damage response (DDR). However, little is known about whether miRNAs might influence sensitivity to PARP inhibitors. To investigate this, we performed a high throughput miRNA mimetic screen, which identified several miRNAs whose over-expression results in sensitization to the clinical PARP inhibitor olaparib. In particular, our findings indicate that hsa-miR-107 and hsa-miR-222 regulate the DDR and sensitise tumour cells to olaparib by repressing expression of RAD51, thus impairing DSB repair by HR. Moreover, elevated expression of hsa-miR-107 has been observed in a subset of ovarian clear cell carcinomas, which correlates with PARP inhibitor sensitivity and reduced RAD51 expression. Taken together, these observations raise the possibility that these miRNAs could be used as biomarkers to identify patients that may benefit from treatment with PARP inhibitors.
Insights
MicroRNAs (miRNAs) can sensitize cancer cells to PARP inhibitors by hindering DNA repair. Specific miRNAs, hsa-miR-107 and hsa-miR-222, show potential as biomarkers for predicting patient response to PARP inhibitor therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against homologous recombination (HR)-deficient cancers (e.g., BRCA1/2 mutations).
- Determinants of PARP inhibitor response beyond HR deficiency are not fully understood.
- MicroRNAs (miRNAs) regulate gene expression and are involved in DNA damage response (DDR).
Purpose of the Study:
- To investigate the role of miRNAs in modulating sensitivity to PARP inhibitors.
- To identify specific miRNAs that enhance tumor cell sensitivity to olaparib.
- To explore the potential of miRNAs as predictive biomarkers for PARP inhibitor therapy.
Main Methods:
- High-throughput miRNA mimetic screening was employed.
- The effect of miRNA overexpression on olaparib sensitivity was assessed.
- RAD51 expression levels and HR repair capacity were evaluated.
Main Results:
- Several miRNAs were identified that sensitize cells to olaparib upon overexpression.
- hsa-miR-107 and hsa-miR-222 were found to repress RAD51, impairing HR-mediated double-strand break (DSB) repair.
- Elevated hsa-miR-107 expression correlated with PARP inhibitor sensitivity and reduced RAD51 in ovarian clear cell carcinomas.
Conclusions:
- hsa-miR-107 and hsa-miR-222 regulate DDR and enhance olaparib sensitivity by targeting RAD51.
- These miRNAs may serve as predictive biomarkers for identifying patients who could benefit from PARP inhibitors.
- Further research into miRNA-mediated regulation of DDR could expand therapeutic strategies.
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