DNA replication and replication stress
Copying three billion letters exactly once means licensing thousands of start points and firing them in waves. Cancers fire too many with too little ink; the forks stall and break. Most classic chemotherapy starves or jams this machinery.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
Printing a 3,000-page book on thousands of small presses at once. Licensing hands out one ticket per press before printing begins; firing starts them in waves. Cancer starts far too many presses with too little ink (nucleotides), so pages smear and tear, and many chemotherapies simply cut off the ink supply or jam the rollers.
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.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 3, Replication and growth machinery: Cancer cells use the same engine as normal cells, only stuck at full throttle.
Copying three billion letters exactly once means licensing thousands of start points and firing them in waves. Cancers fire too many with too little ink; the forks stall and break. Most classic chemotherapy starves or jams this machinery.
DNA replication & origin licensing. Before a cell divides it must copy three billion letters of DNA exactly once, 'licensing' thousands of start points in advance and firing them in waves. Cancers driven by MYC, cyclin E or RAS fire excess start points too fast, and antimetabolites such as 5-FU, topoisomerase poisons such as irinotecan and platinum drugs all jam this copying machinery.
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.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
ATR is a DNA-damage alarm kinase. Blocking it makes tumours with broken repair systems collapse under their own replication stress.
A checkpoint kinase that gives cells time to fix DNA before dividing. Removing it forces damaged cancer cells into a fatal division.
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
CDK4/6 is the engine that pushes a cell to copy its DNA. Blocking it alongside hormone therapy roughly doubled the time hormone-driven breast cancer stays controlled.
TROP2 is a surface glycoprotein present at high levels on most epithelial cancers (breast, lung, urothelial, gastric, pancreatic) and at low levels on normal tissue. It does not drive the cancer; it is a delivery address, used by the approved ADCs sacituzumab govitecan and datopotamab deruxtecan and by sacituzumab tirumotecan, with a TROP2 PET tracer in development to pick patients.
TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- CeralasertibPhase 3
- AzenosertibPhase 3
- AdagrasibApprovedNon-small-cell lung cancerColorectal cancerPancreatic ductal adenocarcinoma
- Avutometinib + defactinibApprovedOvarian cancerLow-grade serous ovarian cancer
- DaraxonrasibApprovedPancreatic ductal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaKRAS G12C-mutant pancreatic ductal adenocarcinoma
- FulzerasibApprovedNon-small-cell lung cancer
- GarsorasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- GlecirasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- Resolution ctDx FIRSTApprovedNon-small-cell lung cancer
- +16 more at KRAS →
- AbemaciclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- DalpiciclibApprovedHR-positive / HER2-negative breast cancer
- PalbociclibApprovedHR-positive / HER2-negative breast cancerHER2-positive breast cancer
- RibociclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- TrilaciclibApprovedSmall-cell lung cancer
- AtirmociclibPhase 3
- LerociclibPhase 3
- TQB3616Phase 3
- +1 more at CDK4/6 →
- Datopotamab deruxtecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerNon-small-cell lung cancer
- Sacituzumab govitecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerBladder & urothelial cancer
- Sacituzumab tirumotecanApprovedTriple-negative breast cancer (TNBC)Non-small-cell lung cancerHR-positive / HER2-negative breast cancer
- BIO-106Phase 2
- EB-NK-301Phase 2
- LCB84Phase 2
- AK146D1Phase 1
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
- GemcitabineApprovedPancreatic ductal adenocarcinomaBladder & urothelial cancerNon-small-cell lung cancer
- Fluorouracil (5-FU)ApprovedColorectal cancerGastric & gastro-oesophageal junction cancerPancreatic ductal adenocarcinoma
- Irinotecan (and liposomal irinotecan)ApprovedColorectal cancerPancreatic ductal adenocarcinomaEwing sarcoma
- Trastuzumab deruxtecanApprovedHER2-positive breast cancerHR-positive / HER2-negative breast cancerGastric & gastro-oesophageal junction cancer
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- Can replication stress be measured in a biopsy to pick patients for ATR/CHK1/WEE1 drugs?
- Why do TOP1-payload ADCs work after topotecan or irinotecan failed?
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2022reviewHallmarks of DNA replication stressMolecular cell
- 2006basicBao 2006: glioma stem cells resist radiotherapy by activating the DNA damage responseNature
- 2002reviewDNA replication in eukaryotic cellsAnnual review of biochemistry
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 3.2 of 56.