DNA replication stress
Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal.
Oncogene activation (MYC, cyclin E, RAS) shortens G1, increases origin firing, and causes fork stalling, ssDNA gaps, and transcription–replication conflicts. ATR senses stalled forks and signals via CHK1 to slow origin firing and stabilise forks; WEE1 restrains CDK1/2. TP53-mutant and CCNE1-amplified cells depend on this axis (G1 checkpoint gone, G2/M checkpoint essential), the rationale for ATR (ceralasertib, camonsertib), CHK1, WEE1 (azenosertib), and PKMYT1 (lunresertib) inhibitors, often with PARP inhibitors or chemotherapy. Toxicity is the recurring limitation because normal proliferating tissue also uses these checkpoints.
In one picture
A photocopier running at triple speed with the paper-jam sensor removed. It keeps working only because a technician (ATR/CHK1/WEE1) constantly clears jams. Remove the technician and it destroys itself.
Diagram
top- ATR inhibitors (ceralasertib, camonsertib) alone and with PARP inhibitors or IO
- WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors in CCNE1-amplified and TP53-mutant tumours
- PARP inhibitors trap forks in HRD tumours (see DDR)
- Gemcitabine and other antimetabolites are classical replication-stress inducers
Notes
top- Leading programmes: Zou (MGH/Duke) and Cimprich (Stanford) on replication-stress signalling; ICR and Dana-Farber early-phase ATR/WEE1 programmes; NKI on CCNE1 dependencies.