ATR inhibition induces anti-tumor effects through replication catastrophe in human cancers

Cell proliferation is sustained and accelerated in cancer, which inherently increases DNA damage. Damaged DNA interfere with replication and transcription, and cells activate DNA damage repair mechanisms to maintain genomic stability. Ataxia telangiectasia and Rad3-related (ATR), ataxia-telangiectasia mutated (ATM), and DNA-dependent protein kinase (DNA-PK) are crucial for the detection of DNA damage and for the initiation of DNA damage response. In particular, ATR detects DNA damage that occurs during the DNA replication process and contributes to replicating stability. ATR inhibitors prevent recovery of replication stress during the DNA replication. As a result, cells cannot endure the extent of DNA damage and eventually cytotoxicity occurs. The anti-tumor effect of an ATR inhibitor, BAY1895344, and the mechanism were investigated in this study. BAY1895344 induced caspase-7-dependent apoptosis and delayed S-phase progression in MDA-MB-453 and MDA-MB-231 cells. Furthermore, single stranded DNA (ssDNA) increased in cells where the cell cycle progression was delayed. In addition, aberrant ssDNA induced DNA damage in S-phase and eventually caused replication catastrophe. Finally, these anti-tumor effects were also proven cell line and patient derived xenograft models. In summary, BAY1895344 has anti-tumor effects through replication catastrophe in human breast cancer cells.