This article reviews the currently used therapeutic strategies to target DNA replication stress for
cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance.
Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of
reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain
genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in
cancer cells. However, the clinical use of
DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the
cancer-associated
isoform of
proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and
peptide agents that specifically target caPCNA can selectively target
cancer cells without significant toxicity to normal cells or experimental animals.