2023 World Conference on Lung Cancer (Posters)-P1.04. Ablative Radiation Induces Distinct Sequential Waves of Mitotic and Innate Immune Death Regulated through DNA Repair Pathways

P1.04. Ablative Radiation Induces Distinct Sequential Waves of Mitotic and Innate Immune Death Regulated through DNA Repair Pathways - PDF(Slides)

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Ablative radiation therapy (ART) is a treatment for cancer patients that involves high-dose radiation. While ART has been shown to improve patient outcomes, the specific mechanisms of cell death induced by this therapy remain unclear. This study aimed to investigate the role of DNA repair mechanisms in determining cell death outcomes in response to ART.<br /><br />The researchers found that ART induces two distinct waves of cell death depending on the cell cycle phase at the time of treatment. They observed that DNA double-strand breaks (DSBs) are the most toxic lesions caused by radiation. In humans, DSBs are repaired by four pathways: non-homologous end joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA), and microhomology-mediated end joining (MMEJ). The researchers showed that HR drives immediate mitotic death, while the combination of NHEJ, SSA, and MMEJ promotes delayed lethality following at least one aberrant cell division.<br /><br />Furthermore, the study demonstrated that the repair pathways can be pharmacologically influenced to modulate the outcomes of ART. For example, inhibiting ATR, a protein involved in DNA damage response, led to a decrease in HR-mediated cell death. Additionally, the researchers found that the genetic status of HR can influence the outcomes of ART. Deficient HR led to a decrease in mitotic death and an increase in interphase death.<br /><br />Overall, this study provides insights into the mechanisms of cell death induced by ART and highlights the importance of DNA repair pathways in determining treatment outcomes. The findings suggest that targeting specific repair mechanisms or considering disease genetics can potentially be utilized to optimize the efficacy of ART.

Asset Subtitle

Harriet Gee

Meta Tag

Speaker Harriet Gee

Topic Tumor Biology: Preclinical Biology - Radiobiology

Keywords

Ablative radiation therapy

cancer treatment

cell death mechanisms

DNA repair pathways

DNA double-strand breaks

non-homologous end joining

homologous recombination

pharmacological modulation

ATR inhibition

genetic status of HR