Inhibition of ATM with KU-55933 Sensitizes Endometrial Cancer Cell Lines to Olaparib

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:

• endometrial cancer
• ATM inhibitor
• PARP inhibitor
• homologous recombination
• synthetic lethality

Abbreviations

FDA, Federal Drug Agency of United States; PARP, Poly ADP-ribose polymerase; SSB, DNA single-strand break; HR, homologous recombination; ATM, Ataxia-telangiectasia mutated; PIKK, phosphatidylinositol 3-kinase-like-protein-kinases; DSB, Double strands break; TNBC, triple negative breast cancer; BRCA, breast invasive carcinoma; CESC, cervical and endocervical cancers; OV, ovarian serous cystadenocarcinoma; UCEC, uterine corpus endometrial carcinoma; HRD, homologous recombination deficiency; DSS, disease-specific survival; DFS, disease free survival; PFS, progress-free survival; OS, overall survival.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Consent for Publication

All the authors agreed to publish this work.

Acknowledgments

Thanks to all the colleagues in Affiliated Hospital of Weifang Medical University who helped with this work.

Disclosure

All the authors declared that there is no competing interest.

Additional information

Funding

This study is supported by soft science program of Weifang Municipal Science and Technology Bureau: 2020RKX085.