Tilting the balance of life and death: navigating DNA replication stress in cancer therapy

Genotoxic anticancer therapies exploit the heightened DNA replication stress of cancer cells. Members of the phosphoinositide-3-kinase-related kinase (PIKK) family, including ATR, ATM and DNA-PKcs, orchestrate the DNA damage response at stalled and broken replication forks, triggering complex signaling cascades that dictate cell fate. p53 plays a pivotal role in regulating the processes of cell cycle, DNA repair and programmed cell death, although p53-independent regulatory mechanisms are also evident. Genotoxic drugs often induce therapy-induced senescence, a state of dynamic and reversible cytostasis that promotes drug resistance and unfavorable patient outcomes. Conversely, severe replication stress culminates in DNA replication catastrophe, a manifestation of irreversible fork collapse with extensive single-stranded DNA accumulation that ultimately results in cell death. Therefore, the magnitude of DNA replication damage and engaged signal transduction pathways determine the outcome of genotoxic therapy. Understanding the molecular basis of the replication stress response that drives therapy-induced senescence versus cell death has far-reaching implications for enhancing the cytotoxic efficacy of anticancer regimens. Here we review the mechanisms of the DNA replication stress response, focusing on pharmacological interventions designed to shift the balance from survival to cell death.