# Harnessing DNA polymerase beta defect enhances synthetic lethality and treatment response in gastric cancer cells: implication for immunotherapy

## TL;DR

This review explores how defects in DNA polymerase beta can improve treatment outcomes in gastric cancer, especially when combined with immunotherapy.

## Contribution

The paper introduces a novel perspective on using POLB defects to enhance synthetic lethality and immunotherapy in gastric cancer.

## Key findings

- POLB deficiency increases genetic vulnerability in cancer cells to targeted therapies.
- PARP1 inhibitors induce DNA damage and immune signals in POLB-deficient cells.
- POLB status could serve as a biomarker to guide treatment in gastric cancer patients.

## 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.