Determination of anti-cancer effect of elimusertib ATR inhibitor on triple-negative breast cancer

INTRODUCTION AND OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with a more aggressive clinical behavior than other breast cancer subtypes, and therefore resistant to current treatment options. Genomic instability in cancer cells is dependent on the activity of DNA damage response and repair mechanisms. For this reason, new treatment approaches targeting Ataxia telangiectasia and Rad3-related (ATR) inhibition in cancer treatment have attracted attention in recent years. In the current thesis, it is aimed for the first time to determine the anti-cancer effect of Elimusertib, an ATR inhibitor, on MDA-MB231 TNBC and control cells. MATERIALS AND METHODS: After the cytotoxic effect of Elimusertib on MDA-MB231 TNBC and MCF-10A control cells was determined by WST-1 analysis, its effect on apoptosis was analyzed with Annexin V, cell cycle analyzes and acridine orange/propidium iodide staining. Mitochondrial damage was assessed by Mitotracker staining and the quantification of intracellular reactive oxygen species. Additionally, its effect on ATR-Chk1 DNA damage response and apoptotic death was elucidated by western blot analysis at the molecular level. RESULTS: Elimusertib significantly decreased the viability of MDA-MB-231 and MCF-10A cells, dose and time dependently (p<0.05). It was determined that Elimusertib caused early and late apoptotic death, arrest in G0/G1 phase and mitochondrial damage in TNBC cells. Additionally, Elimussertib mediated apoptotic death by suppressing the ATR-based DNA damage response in TNBC cells was analyzed at the protein level. CONCLUSION: In this study, the anti-cancer effect of Elimusertib as an ATR inhibitor was determined for the first time on TNBC cells. The findings show that Elimusertib effectively inhibits the ATR-based Chk1 pathway in TNBC cells and may be an innovative treatment option, especially in p53 mutant TNBC patients. Keywords: DNA damage response, ATR, Cell cycle, Apoptosis, Triple negative breast cancer.