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A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor
Nicholas C Turner1, Christopher J Lord, Elizabeth Iorns
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Abstract:
Inhibitors of poly (ADP-ribose)-polymerase-1 (PARP) are highly lethal to cells with deficiencies in BRCA1, BRCA2 or other components of the homologous recombination pathway. This has led to PARP inhibitors entering clinical trials as a potential therapy for cancer in carriers of BRCA1 and BRCA2 mutations. To discover new determinants of sensitivity to these drugs, we performed a PARP-inhibitor synthetic lethal short interfering RNA (siRNA) screen. We identified a number of kinases whose silencing strongly sensitised to PARP inhibitor, including cyclin-dependent kinase 5 (CDK5), MAPK12, PLK3, PNKP, STK22c and STK36. How CDK5 silencing mediates sensitivity was investigated. Previously, CDK5 has been suggested to be active only in a neuronal context, but here we show that CDK5 is required in non-neuronal cells for the DNA-damage response and, in particular, intra-S and G(2)/M cell-cycle checkpoints. These results highlight the potential of synthetic lethal siRNA screens with chemical inhibitors to define new determinants of sensitivity and potential therapeutic targets.
Insights
PARP inhibitors are effective cancer treatments for BRCA-mutated cancers. A screen revealed that inhibiting kinases like CDK5 sensitizes cells to PARP inhibitors, uncovering new therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Poly (ADP-ribose)-polymerase-1 (PARP) inhibitors show high efficacy in cancer cells with homologous recombination deficiencies, such as those with BRCA1/BRCA2 mutations.
- This has led to PARP inhibitors being investigated in clinical trials for treating BRCA-mutated cancers.
Purpose of the Study:
- To identify novel determinants of sensitivity to PARP inhibitors.
- To explore the role of cyclin-dependent kinase 5 (CDK5) in DNA damage response and cell-cycle checkpoints.
Main Methods:
- A short interfering RNA (siRNA) screen was conducted to identify genes that, when silenced, confer synthetic lethality with PARP inhibitors.
- The function of CDK5 in non-neuronal cells concerning DNA damage response was investigated.
Main Results:
- The screen identified several kinases, including CDK5, MAPK12, PLK3, PNKP, STK22c, and STK36, whose silencing significantly sensitized cells to PARP inhibitors.
- CDK5 was found to be essential in non-neuronal cells for DNA-damage response, specifically for intra-S and G(2)/M cell-cycle checkpoints.
Conclusions:
- Synthetic lethal siRNA screens coupled with chemical inhibitors are valuable for discovering new sensitivity determinants and potential therapeutic targets.
- CDK5 plays a crucial role in DNA repair pathways in non-neuronal cells, suggesting its potential as a therapeutic target in conjunction with PARP inhibitors.
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