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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Harnessing DNA polymerase beta defect enhances synthetic lethality and treatment response in gastric cancer cells:
Aashirwad Shahi1, Shengyuan Zhao2, Dawit Kidane1
1Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, United States.
Abstract:
Gastric cancer remains a highly prevalent and accounts for a notable proportion of global cancer mortality. Both Intrinsic and exogenous agents can exacerbate reactive oxygen species (ROS) related oxidized DNA base lesions and single stranded DNA breaks (SSBs). Base excision repair (BER) serves as the primary defense mechanism for repairing DNA damage induced by oxidative stress. DNA polymerase beta (Pol β) plays a critical role in BER and non-homologous end joining repair pathways. The Pol β is the first perform gap-filling DNA synthesis by its polymerase activity and then cleave a 5'-deoxyribose-5-phosphate (dRP) moiety via its dRP lyase activity. Furthermore, defect in POLB promotes genetic liability of the cancer cells for different targeted and synthetic lethality-based treatment strategies. In this review, we have provided a potential example to illustrate the mechanistic insight how PARP1 inhibitor (Olaparib) induces replication associated double strand breaks in POLB deficient cells and DNA mediated innate immune signal activation that likely enhances immune based therapy. Based on our previously published data and the current recent findings, POLB status of the patient likely provide genetic indicators to stratify gastric cancer patient. Overall, in this review article, we presented a new direction to highlight the opportunity to exploit POLB genetic defect in cancer cells to enhance treatment response and to explore synergistic effect to target gastric cancer cells that harbor aberrant DNA polymerase beta function with immune based therapeutic strategy.
Insights
Gastric cancer cells with DNA polymerase beta (POLB) defects are vulnerable to PARP1 inhibitors, leading to DNA damage and immune activation. Targeting POLB defects offers a novel strategy to enhance gastric cancer treatment response and immune-based therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer is a leading cause of cancer mortality globally.
- Oxidative stress causes DNA damage, including oxidized bases and single-stranded breaks.
- Base excision repair (BER) is crucial for repairing oxidative DNA damage, with DNA polymerase beta (Pol β) playing a key role.
Purpose of the Study:
- To review the role of DNA polymerase beta (POLB) in gastric cancer.
- To explore the therapeutic potential of targeting POLB defects.
- To investigate the interplay between POLB deficiency, PARP1 inhibition, and immune response in gastric cancer.
Main Methods:
- Review of existing literature and previously published data.
- Mechanistic insights into how PARP1 inhibitors induce DNA damage in POLB-deficient cells.
- Analysis of DNA-mediated innate immune signaling activation.
Main Results:
- POLB deficiency creates genetic liabilities in cancer cells, making them susceptible to targeted therapies.
- PARP1 inhibitor (Olaparib) induces replication-associated double-strand breaks in POLB-deficient gastric cancer cells.
- This DNA damage triggers innate immune signaling, potentially enhancing immunotherapy.
Conclusions:
- POLB status can serve as a genetic indicator for stratifying gastric cancer patients.
- Exploiting POLB genetic defects can enhance treatment response in gastric cancer.
- Targeting POLB-deficient gastric cancer cells with immune-based strategies may offer synergistic effects.
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