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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.
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.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It defines a small group with an excellent prognosis that no repair immunohistochemistry panel or MSI assay will find, and it is the main argument for sequencing rather than staining alone in younger patients.
POLE and POLD1 are now on polyposis and colorectal germline panels, and the paper explains why a patient with many adenomas and an entirely normal mismatch repair panel still needs sequencing.
Shares WEE1, MYC, MYC, p53 / RB / cell-cycle checkpoint and the tag mechanism.
Shares Telomere maintenance & replicative immortality, The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53 and the tag mechanism.
Shares MYC, MYC, Dana-Farber Brigham Cancer Center and the tag mechanism.
Shares The Francis Crick Institute, MYC, MYC and the tag mechanism.
Shares SWI/SNF chromatin remodelling, The Francis Crick Institute, TP53 and the tag mechanism.
Shares PARP, Dana-Farber Brigham Cancer Center, PARP inhibitors, TP53 and the tag mechanism.
Shares Attack extrachromosomal DNA, the engine of oncogene amplification, The Francis Crick Institute, Chromosomal instability & aneuploidy, TP53 and the tag mechanism.