The cell cycle and CDKs
Division runs on a clock of cyclins and CDKs firing in order. Cancers flood the first step (cyclin D) or remove the throttle (p16). CDK4/6 inhibitors slow the clock and changed breast cancer treatment.
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.
An engine with four cylinders that must fire in sequence. Cyclins are the fuel injected into each cylinder in turn and burned away; CDKs are the pistons. p16 and p21 are the hand on the throttle. Cancers flood the first cylinder (cyclin D) or remove the throttle hand (CDKN2A).
A checkpoint at a border: p53 is the inspector who halts traffic when something looks wrong, MDM2 is the manager who keeps sending the inspector home, RB is the barrier arm, and CDK4/6 is the motor that lifts it. Cancers bribe the inspector (TP53 mutation) or hot-wire the motor (cyclin D amplification).
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.
Division runs on a clock of cyclins and CDKs firing in order. Cancers flood the first step (cyclin D) or remove the throttle (p16). CDK4/6 inhibitors slow the clock and changed breast cancer treatment.
The cell-cycle engine (cyclins & CDKs). Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it.
p53 / RB / cell-cycle checkpoint. The p53 and RB checkpoints are the cell's brakes. p53 senses damage and stops the cell from copying itself; RB holds the cell at the G1 gate until CDK4/6 unlocks it. Cancers cut these brakes.
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.
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.
A checkpoint kinase that gives cells time to fix DNA before dividing. Removing it forces damaged cancer cells into a fatal division.
The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy.
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.
ATR is a DNA-damage alarm kinase. Blocking it makes tumours with broken repair systems collapse under their own replication stress.
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.
- AbemaciclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- PalbociclibApprovedHR-positive / HER2-negative breast cancerHER2-positive breast cancer
- RibociclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- AtirmociclibPhase 3
- DalpiciclibApprovedHR-positive / HER2-negative breast cancer
- TrilaciclibApprovedSmall-cell lung cancer
- LerociclibPhase 3
- TQB3616Phase 3
- +1 more at CDK4/6 →
- AzenosertibPhase 3
- CamizestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- ElacestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- ExemestaneApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- Fluoroestradiol F-18 (FES PET)ApprovedHR-positive / HER2-negative breast cancer
- FulvestrantApprovedHR-positive / HER2-negative breast cancer
- Goserelin / leuprolide (ovarian function suppression)ApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- ImlunestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- +9 more at Estrogen receptor (ERα) →
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
- CeralasertibPhase 3
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
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.
- Which patients need a CDK4/6 inhibitor at all, and who is cured by endocrine therapy alone?
- Will CDK2 inhibitors overcome cyclin E-driven resistance safely?
- early clinicalindustryAn open-science consortium on the undruggable drivers, open until a candidate
Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.
- early clinicalCDK4-selective inhibitors as the new first-line backbone
If a CDK4-only drug matches CDK4/6 inhibitors on efficacy with less neutropenia, continuous dosing and better adherence could translate into longer control.
- early clinicalresearchExtend p53 reactivation beyond the Y220C mutation
One faulty version of the p53 guardian protein can now be repaired by a drug that plugs a hole in it. Systematically hunting for similar holes in other faulty versions could help far more patients.
- speculativeresearchDegrade the damaged p53 protein rather than trying to repair it
Some faulty p53 proteins do not just stop protecting the cell; they actively help the cancer. Removing them entirely may be easier than fixing them.
- speculativephilanthropyMilestone prizes for first-in-class mechanisms reaching human proof of concept
Pay a fixed prize, of tens of millions, to the first team to show that a completely new way of attacking cancer works in patients, so that the riskiest early bets are rewarded even before a product exists.
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
- 2020rctmonarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancerJournal of Clinical Oncologychanged practice
- 2009reviewCell cycle, CDKs and cancer: a changing paradigmNature Reviews Cancer
- 2000reviewVogelstein, Lane and Levine 2000: surfing the p53 networkNature
- 1999reviewSherr and Roberts 1999: CDK inhibitors as regulators of the G1 phaseGenes and Development
- 1997reviewLevine 1997: p53, the cellular gatekeeper for growth and divisionCell
- 1993basicEl-Deiry 1993: WAF1, the gene through which p53 stops cell divisionCell
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 3.1 of 56.