The ATR inhibition by Elimusertib enhances the radiosensitivity of MDA-MB-231 triple negative breast cancer in vitro

Abstract

Purpose

DNA damage response (DDR) is the principal mechanism regulating genomic stability and cell cycle checkpoint activation by coordinating DNA repair and apoptotic pathways. Ataxia telangiectasia and Rad3-related protein (ATR) play a significant role in the DDR due to its capability to detect a wide spectrum of DNA damage. Therefore, targeting DDR, specifically ATR, is a promising therapeutic strategy in cancer treatment. Furthermore, the inhibition of ATR sensitizes cancer cells to radiotherapy (RT). Herein, we, for the first time, investigated the synergistic effects of Elimusertib (BAY-1895344) as a highly potent selective ATR inhibitor with RT combination in triple-negative breast cancer (TNBC), in vitro.

Methods

MDA-MB-231 TNBC cells were firstly treated with different concentrations of Elimusertib for 24 h and then exposed to 4 and 8 Gy of X-ray irradiation. After post-irradiation for 72 h, WST-1, Annexin V, cell cycle, acridine orange/propidium iodide, mitochondria staining and western blot analysis were conducted.

Results

Our findings showed that 4 Gy irradiation and lower doses (especially 2 and 4 nM) of Elimusertib combination exerted a considerable anticancer activity at 72 h post-irradiation through apoptotic cell death, marked nuclear and mitochondrial damages and the suppression of ATR-Chk1 based DDR mechanism.

Conclusion

ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.

Keywords:

• Triple negative breast cancer
• DNA damage response
• ATR
• radiotherapy
• apoptosis

Disclosure statement

No potential conflict of interest was reported by the author(s). All authors contributed to the article and approved the submitted version.

Data availability statement

The original contributions presented in the study are included in the article and as supplementary material. Further inquiries can be directed to the corresponding author.

Additional information

Funding

This work was supported by the [Research Fund of Sakarya University] under Grant [Number: 2022-9-33-47].

Notes on contributors

Gamze Guney Eskiler

Gamze Guney Eskiler, PhD, is an Associate Professor in Department of Medical Biology at Sakarya University, Sakarya, Türkiye. Her research have focused on cancer cell biology, drug resistance mechanisms, nanoparticle based drug delivery systems, cell death types and pathways and combine treatment strategies in cancer.

Hatice Halis

Hatice Halis, is radiation oncologist at Sakarya Training and Research Hospital, Sakarya, Türkiye.

Kaan Furkan Hamarat

Kaan Furkan Hamarat is a medical student at the Sakarya University, Sakarya, Türkiye.

Rabia Rana Derlioglu

Rabia Rana Derlioglu is graduate student at Institute of Health Sciences, Sakarya University, Sakarya, Türkiye.

Berat Tugrul Ugurlu

Berat Tugrul Ugurlu is physics expert and studying at Medko Oncology, Istanbul, Türkiye.

Ayten Haciefendi

Ayten Haciefendi, MSc, is a expert in cancer biology and studying at Department of Medical Biology, Bursa Uludag University, Bursa, Türkiye.