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.
DNA damage activates ATM/ATR → CHK2/CHK1 → p53 stabilisation (MDM2 degrades p53 normally). p53 induces p21, which inhibits CDK4/6-cyclin D and CDK2-cyclin E, keeping RB bound to E2F and the cell in G1. Cyclin D1 amplification, CDK4 amplification, CDKN2A (p16) loss, RB loss, and TP53 mutation (50% of cancers) each release the brake. CDK4/6 inhibitors re-impose it in RB-intact HR+ breast cancer; WEE1 and PLK1 inhibitors exploit G2/M dependence in TP53-mutant cells; MDM2 inhibitors reactivate wild-type p53.
In one picture
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).
Diagram
top- CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib)
- WEE1 inhibitors (azenosertib) and PLK1 inhibitors in TP53-mutant tumours
- MDM2 inhibitors (brigimadlin) in TP53-wild-type tumours
- p53 Y220C reactivator rezatapopt
- CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease