Chemotherapeutic DNA-damaging agents targeting replication are widely used but predictive rationales for drug combinations and patient selection still need clinical definition. Here, we review cancer-associated replication stress (RepStress) and its genomic signature, and propose how to utilize RepStress-targeted therapies in the context of ATR inhibitors and Schlafen 11 (SLFN11).

Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.