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Published on: May 27, 2021
Synthetic Lethality - Its Current Application and Potential in Oncological Treatment
Background:
Synthetic lethality is a gene interaction where a defect in one of the interacting genes is compatible with cell viability, whereas the disruption of both genes leads to cell death. The discovery of the lethal effect of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutant cells has opened an important direction in the development of targeted therapy in oncology. The PARP inhibitor olaparib has become the first registered drug for recurrent high-grade serous ovarian cancer treatment based on synthetic lethality that has reached the clinic. Current research focuses on the combination of PARP inhibitors and inhibitors of kinases, which control the cell cycle, to prevent or overcome resistance to PARP inhibitors. There are also ongoing clinical trials which examine PARP inhibitor treatment in other types of cancers including tumours presenting the so-called BRCAness phenotype. Screenings for new synthetic lethalities which could serve as potential targets for new drug development have improved with the CRISPR/Cas9 technology, but another key problem persists in the screening efforts, namely the incomplete penetrance of synthetic lethality throughout a tumour cell population.
Purpose:
This paper summarises the current application of synthetic lethality principles in oncology and discusses the challenges in research focused on potential new drugs based on synthetic lethality.
Insights
Synthetic lethality, a gene interaction causing cell death when both genes are disrupted, is key to targeted cancer therapies like PARP inhibitors. Challenges remain in identifying new synthetic lethalities and ensuring consistent drug effects across all tumor cells.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Synthetic lethality involves gene interactions where disrupting one gene is tolerated, but disrupting both leads to cell death.
- The success of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-mutated cancers highlights synthetic lethality's therapeutic potential.
- Olaparib, a PARP inhibitor, is a clinically approved treatment for ovarian cancer, demonstrating the translation of synthetic lethality principles into practice.
Purpose of the Study:
- To summarize the current applications of synthetic lethality in oncology.
- To discuss the challenges and future directions in developing new drugs based on synthetic lethality principles.
Main Methods:
- Review of current research and clinical applications of synthetic lethality in cancer treatment.
- Discussion of technological advancements, such as CRISPR/Cas9, in identifying synthetic lethal interactions.
- Analysis of challenges, including incomplete penetrance of synthetic lethality in tumor cell populations.
Main Results:
- PARP inhibitors represent a successful clinical application of synthetic lethality, particularly in BRCA-mutated cancers.
- Ongoing research explores combinations of PARP inhibitors with cell cycle kinase inhibitors to enhance efficacy and overcome resistance.
- Clinical trials are expanding to investigate PARP inhibitor utility in other cancer types, including those with a 'BRCAness' phenotype.
Conclusions:
- Synthetic lethality offers a promising framework for targeted cancer therapy development.
- Further research is needed to address challenges like incomplete penetrance to fully realize the potential of synthetic lethality-based drugs.
- Advancements in screening technologies and combination therapies are crucial for expanding the clinical utility of synthetic lethality.
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