Abstract
Background:
Endometrial cancer (EC) is one of the most prevalent gynecologic cancers, which poses a serious threat to women's health worldwide. Olaparib, the first FDA-approved PARP inhibitor for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers, triggers apoptosis of cancer cells through synthetic lethality by inhibiting PARP1/2 enzymatic activity and BRCA1/2-dependent homologous recombination (HR) repair deficiency. However, the synergistic lethal effects between Olaparib and inhibitors of other DNA damage response proteins, such as ATM, PTEN and RAD51, are still unknown.
Aim:
Exploring the synergistic lethal effect between Olaparib and KU-55933 on EC.
Methods:
The GEPIA database was used to test EC patient survival rate. CCK8 was used for cell viability assays. Western blot was used for examining gene levels. The wound healing assay was used to detect cell migration ability. Flow cytometry was used for detecting the apoptosis rate. All experimental conditions were repeated independently in triplicate and analyzed in three separate experiments.
Results:
In this study, we discovered that the frequency of ATM alterations in endometrial cancer reaches nearly 20% and that there is a positive correlation between ATM alterations and prognosis. Furthermore, we discovered that endometrial cells with low expression levels of ATM are sensitive to Olaparib. Treatment with KU-55933, a specific inhibitor of ATM, significantly enhanced the sensitivity of endometrial cancer cells to Olaparib, as evidenced by colony formation, cell migration and apoptosis assay. Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation.
Conclusion:
Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.
Keywords:
ATM inhibitor; PARP inhibitor; endometrial cancer; homologous recombination; synthetic lethality.