Targeting the Ataxia Telangiectasia and Rad3 Signaling Pathway to Overcome Chemoresistance in Cancer

The ataxia telangiectasia and Rad3-related (ATR) signaling pathway controls DNA replication initiation and cell-cycle progression and coordinates the repair of damaged replication forks. It is, therefore, an important regulator of the cellular response to DNA replication stress. Inhibition of the ATR signaling pathway results in dysregulation of replication origin initiation, leading to exacerbation of replication stress manifested by the slowing and stalling of replication forks, and enhanced susceptibility to fork breakage. Accordingly, inhibition of ATR or its downstream effector Chk1 is potently cytotoxic to tumor cells with heightened levels of endogenous replication stress, particularly in tumors with DNA damage response or cell-cycle checkpoint defects. This results in a functional addiction to the ATR pathway. Small-molecule inhibitors of ATR and Chk1 are currently under investigation. Preclinical studies of these inhibitors have demonstrated single-agent efficacy across a range of malignancies, and results from clinical trials are emerging. In addition, markers of sensitivity to ATR and Chk1 inhibitors are being identified, and novel chemotherapeutic combinations involving these agents are being developed. A number of unresolved issues notwithstanding, the ATR signaling pathway represent a promising target for cancer therapeutics.