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Published on: May 27, 2021
Synthetic Lethality Targeting Polθ
Małgorzata Drzewiecka1, Gabriela Barszczewska-Pietraszek1, Piotr Czarny2
1Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.
Abstract:
Research studies regarding synthetic lethality (SL) in human cells are primarily motivated by the potential of this phenomenon to be an effective, but at the same time, safe to the patient's anti-cancer chemotherapy. Among the factors that are targets for the induction of the synthetic lethality effect, those involved in DNA repair seem to be the most relevant. Specifically, when mutation in one of the canonical DNA double-strand break (DSB) repair pathways occurs, which is a frequent event in cancer cells, the alternative pathways may be a promising target for the elimination of abnormal cells. Currently, inhibiting RAD52 and/or PARP1 in the tumor cells that are deficient in the canonical repair pathways has been the potential target for inducing the effect of synthetic lethality. Unfortunately, the development of resistance to commonly used PARP1 inhibitors (PARPi) represents the greatest obstacle to working out a successful treatment protocol. DNA polymerase theta (Polθ), encoded by the POLQ gene, plays a key role in an alternative DSB repair pathway-theta-mediated end joining (TMEJ). Thus, it is a promising target in the treatment of tumors harboring deficiencies in homologous recombination repair (HRR), where its inhibition can induce SL. In this review, the authors discuss the current state of knowledge on Polθ as a potential target for synthetic lethality-based anticancer therapies.
Insights
Synthetic lethality offers a targeted cancer therapy approach. Inhibiting DNA polymerase theta (Polθ) in homologous recombination repair-deficient tumors can induce synthetic lethality, overcoming resistance to other therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Synthetic lethality (SL) is a promising strategy for cancer chemotherapy, targeting cancer cells while sparing normal cells.
- DNA repair pathways are key targets for inducing SL, especially in cancer cells with mutations in canonical repair mechanisms.
- Resistance to current therapies like PARP1 inhibitors (PARPi) necessitates novel therapeutic targets.
Purpose of the Study:
- To review the potential of DNA polymerase theta (Polθ) as a target for synthetic lethality-based cancer therapies.
- To explore the role of Polθ in the theta-mediated end joining (TMEJ) DNA repair pathway.
- To discuss the implications of Polθ inhibition in tumors with homologous recombination repair (HRR) deficiencies.
Main Methods:
- Literature review of current research on synthetic lethality and DNA repair pathways.
- Analysis of the role of DNA polymerase theta (Polθ) in double-strand break (DSB) repair.
- Examination of therapeutic strategies targeting Polθ in cancer treatment.
Main Results:
- Polθ is crucial for the alternative TMEJ DNA repair pathway.
- Inhibition of Polθ can induce synthetic lethality in homologous recombination repair (HRR)-deficient cancer cells.
- Polθ represents a potential therapeutic target to overcome resistance to existing cancer treatments.
Conclusions:
- DNA polymerase theta (Polθ) is a viable target for developing novel synthetic lethality-based anticancer therapies.
- Targeting Polθ offers a strategy to treat tumors resistant to current therapies, particularly those with HRR deficiencies.
- Further research into Polθ inhibitors is warranted for effective cancer treatment protocols.
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