Inhibition of DNA ligase IV affects the DNA damage repair pathway and decreases the sensitivity of olaparib to platinum-sensitive BRCA wild-type ovarian cancer

Ovarian cancer is one of the most common gynecologic malignancies, and the mortality rate has always been the highest among gynecologic malignancies. Currently, the initial treatment mode after the first diagnosis of ovarian cancer is tumor cytoreductive surgery, platinum-based chemotherapy, and targeted drug maintenance therapy. Although PARP inhibitors are an important approach to maintenance therapy, relapse occurs in patients after a period of treatment. PARP inhibitors mainly exert anti-tumor effects by inhibiting the repair of tumor cell DNA damage to achieve synthetic lethality. After DNA damage, repair primarily occurs through two pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). DNA ligase IV, as a crucial enzyme in NHEJ, plays a role in connecting DNA fragments during the DNA repair process. Through bioinformatics analysis, we found that the use of olaparib in platinum-sensitive BRCA wild-type ovarian cancer cells leads to a decrease in the expression levels of DNA ligase IV in patients. Furthermore, cell experiments revealed that the expression levels of DNA ligase IV affect the sensitivity of ovarian cancer cells to olaparib. Specifically, when the expression levels of DNA ligase IV are reduced, the sensitivity of ovarian cancer to olaparib decreases. This suggests that BRCA wild-type ovarian cancer patients with low expression of DNA ligase IV may not respond well to PARP inhibitors. Through comet assays and other methods, it was discovered that a decrease in DNA ligase IV levels makes DNA less susceptible to damage in platinum-sensitive BRCA wild-type cells. Additionally, alterations in DNA ligase IV affect the related pathway genes of DNA damage repair in platinum-sensitive BRCA ovarian cancer, resulting in changes in DNA damage repair mechanisms. Therefore, the changes in NHEJ caused by DNA ligase IV may be one of the reasons for the sensitivity of BRCA wild-type ovarian cancer cells to PARP inhibitors. In the future, it may be possible to improve the efficacy of PARP inhibitors in BRCA wild-type ovarian cancer patients by influencing changes in the expression levels of DNA ligase IV.