Synergistic radiosensitizing effect of BR101801, a specific DNA-dependent protein kinase inhibitor, in various human solid cancer cells and xenografts

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• DNA-dependent protein kinase (DNA-PK) is crucial for DNA damage repair (DDR) via non-homologous end-joining (NHEJ).
• DNA-PK inhibition offers a strategy to overcome radioresistance and chemoresistance in cancer treatment.

Purpose of the Study:

• To evaluate BR101801, a novel DNA-PK inhibitor, as a radiosensitizer in human solid cancers.
• To investigate the mechanisms underlying BR101801's radiosensitizing effects.

Main Methods:

• In vitro studies using various human solid cancer cell lines.
• In vivo studies using a human solid cancer xenograft model.
• Assessment of cell cycle arrest, cell death, DNA repair pathways, and protein phosphorylation.

Main Results:

• BR101801 significantly enhanced ionizing radiation (IR)-induced genomic instability and cell death.
• BR101801 induced G2/M cell cycle arrest and autophagic cell death.
• BR101801 inhibited DNA-PK phosphorylation and reduced BRCA2 protein levels, impacting both NHEJ and homologous recombination (HR) repair.
• Combination therapy with BR101801 and IR suppressed tumor growth in vivo.

Conclusions:

• BR101801 is a potent and selective DNA-PK inhibitor with significant radiosensitizing effects in human solid cancers.
• BR101801 demonstrates synergistic activity with IR, offering a promising strategy for clinical applications in cancer therapy.