What Is Synthetic Lethality?
Synthetic lethality refers to a genetic principle where the simultaneous disruption of two genes or pathways leads to cell death, while the disruption of either gene alone does not. It is a precision treatment that provides promised results.
The concept of synthetic lethality can be divided into two categories:
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Synthetic lethality occurs between the tumor suppressor genes and their partner gene during loss-of-function mutations. This is a genetic interaction when two or more mutations cause cell death, whereas a single mutation in any gene does not.
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Synthetic dosage lethality occurs between the oncogene (a mutated gene that can potentially transform into a tumor cell) and its partner gene. This is a genetic interaction where overexpression of an oncogene combined with the under-expression of its partner gene destroys the tumor cell.
In cancer therapy, synthetic lethality utilizes the genetic vulnerabilities of cancer cells by taking advantage of the genetic variations between cancer cells and normal cells. This approach aims to selectively kill cancer cells while keeping healthy ones safe, minimizing side effects, and improving the overall therapeutic outcome. Overall, synthetic lethality and synthetic dosage lethality provide important guidance for identifying cancer-specific treatments and uncovering cancer-specific susceptibilities.
How Does Synthetic Lethality Work?
The basis of synthetic lethality lies in the genetic changes that occur in cancer cells. These changes can cause the loss of function of certain genes, creating a dependency on alternative pathways for survival. When two such pathways are interconnected, disrupting one can be tolerated by cancer cells as long as the other remains intact.
However, when both pathways are simultaneously disrupted, it becomes lethal for the cancer cells. The interaction between poly (ADP-ribose) polymerase (PARP) and breast cancer susceptibility gene 1 (BRCA1/2) mutations is an example of synthetic lethality in cancer therapy involving DNA repair pathways.
BRCA1 and BRCA2 are two important genes involved in repairing double-strand DNA breaks. When these genes are intact, normal cells ensure proper DNA repair. However, in cancer cells with BRCA1 or 2 mutations, the homologous recombination repair pathway is compromised, making the cells dependent on the PARP pathway for DNA repair. This creates a synthetic lethality scenario where inhibiting PARP in BRCA-mutated cancer cells disrupts their ability to repair DNA, leading to cell death. PARP inhibitors, like Olaparib, use this synthetic lethality to selectively target BRCA-mutated tumors, such as certain breast and ovarian cancers.
Other common examples of potential synthetic lethal pairs in various cancer types are the following:
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In lung cancer, synthetic lethality has been noted between KRAS mutations and the loss of function of the STK11 gene.
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Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins are key regulators of DNA damage response. In cancer cells with ATM deficiencies, inhibition of ATR has shown promising results.
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The combination of mutations in the WNT signaling pathway and the inactivation of the tumor suppressor gene TP53 has been utilized for synthetic lethal targeting in colorectal cancer.
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The tumor suppressor p53 plays an important role in cell cycle regulation and DNA repair. In cancers with p53 mutations, inhibiting the protein kinase Wee1 can cause synthetic lethality by preventing cell cycle arrest and inducing mitotic catastrophe.
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The oncogene c-Myc is frequently overexpressed in various cancers, causing genomic instability. Combining CHK1 inhibitors with c-Myc amplification disrupts DNA repair and cell cycle regulation, driving synthetic lethality in these cancer cells.
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In gliomas, isocitrate dehydrogenase (IDH) gene mutations are common. Inhibitors targeting mutant IDH utilize synthetic lethality by blocking the oncometabolite 2-hydroxyglutarate production, promoting tumor production or formation.
What Are the Clinical Implications of Synthetic Lethality?
The application of synthetic lethality in cancer therapy has shown considerable promise in preclinical studies and clinical trials.
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Synthetic lethality helps in the development of more precise and effective cancer treatments. By identifying synthetic lethal gene pairs and pathways specific to different cancer types, researchers and pharmaceutical companies can design targeted therapies that utilize these vulnerabilities.
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Synthetic lethality-based treatments have the potential to be highly personalized. Genetic testing can identify specific gene mutations or alterations in a patient's tumor, allowing healthcare professionals to personalize treatment strategies to individual genetic profiles.
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Drug resistance is a common challenge in cancer treatment. However, synthetic lethality-based therapies may help to overcome it. Cancer cells that develop resistance to any treatment may still be vulnerable to synthetic lethal combinations.
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Synthetic lethality mostly targets genetic vulnerabilities in cancer cells without disturbing healthy cells. Therefore, side effects are less likely than traditional therapies like chemotherapy.
What Are the Challenges of Synthetic Lethality?
Synthetic lethality is evolving and showing promising results. However, they also face several challenges for its widespread implementation:
However, several challenges must be addressed for its widespread implementation:
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Identifying the appropriate patient populations with specific genetic vulnerabilities is a herculean task. Genetic testing and biomarker identification are necessary to rule out eligible patients.
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It is also noted that cancer cells can develop resistance to synthetic lethality-based therapies over time. So, it is necessary to identify the resistance mechanisms and develop strategies to overcome them.
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Synthetic lethality-based therapies are designed to be more selective. However, off-target effects and toxicity must be carefully monitored and managed.
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Many synthetic lethal therapies are still in the early stages of clinical development, and their long-term safety and efficacy are yet to be fully established.
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Many synthetic lethality approaches involve different drug combinations, potential drug interactions, and increasing the complexity of treatment regimens.
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Synthetic lethality-based therapies can be expensive, limiting their accessibility to a broader population of cancer patients.
What Are the Future Perspectives on Synthetic Lethality?
As there is development and expansion in many fields of cancer, such as genetics and molecular pathways, this paves the way for more synthetic lethal interactions. In the future, synthetic lethality may extend beyond DNA repair and cell cycle regulation. There is ongoing research to identify synthetic lethal interactions involving other essential pathways, such as epigenetics, metabolism, and immune regulation. This widened scope may lead to more effective treatment options for different types of cancers.
Conclusion
Synthetic lethality is a revolutionary approach in the field of cancer treatment. It offers more precise and effective treatments with minimal side effects. As the knowledge of genetic alterations and molecular pathways widens, so will the ability to identify and exploit synthetic lethal interactions. In the future, there is great scope for synthetic lethality in cancer therapy.
