# p53 / RB / cell-cycle checkpoint

Source: https://onco.cc/pathways/p53-cell-cycle/  
OnCo record `p53-cell-cycle` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: 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).
- Interventions: 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cell_cycle_checkpoint
- Wikipedia: https://en.wikipedia.org/wiki/Cell_cycle_checkpoint

## Connected records

- cancers: [Adrenocortical carcinoma](https://onco.cc/cancers/adrenocortical/), [Ampullary cancer (ampulla of Vater)](https://onco.cc/cancers/ampullary/), [Basal-like 1 triple-negative breast cancer (BL1)](https://onco.cc/cancers/tnbc-basal-like-1/), [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Cutaneous squamous cell carcinoma](https://onco.cc/cancers/cutaneous-scc/), [Diffuse midline glioma, H3 K27-altered (including DIPG)](https://onco.cc/cancers/dipg-dmg/), [Ewing sarcoma](https://onco.cc/cancers/ewing-sarcoma/), [Extensive-stage small-cell lung cancer](https://onco.cc/cancers/extensive-stage-sclc/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors](https://onco.cc/cancers/ipmn-cystic-precursors/), [Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma)](https://onco.cc/cancers/ipmn-associated-carcinoma/), [Limited-stage small-cell lung cancer](https://onco.cc/cancers/limited-stage-sclc/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [Merkel cell carcinoma](https://onco.cc/cancers/merkel-cell-carcinoma/), [Mesothelioma](https://onco.cc/cancers/mesothelioma/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Osteosarcoma](https://onco.cc/cancers/osteosarcoma/), [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Penile cancer](https://onco.cc/cancers/penile/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Retinoblastoma](https://onco.cc/cancers/retinoblastoma/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/), [Wilms tumour (nephroblastoma)](https://onco.cc/cancers/wilms-tumor/)
- targets: [ATM](https://onco.cc/targets/atm/), [ATR](https://onco.cc/targets/atr/), [CDK4/6](https://onco.cc/targets/cdk4-6/), [CDKN1A](https://onco.cc/targets/cdkn1a/), [E2F7](https://onco.cc/targets/e2f7/), [MDM2](https://onco.cc/targets/mdm2/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/), [WEE1](https://onco.cc/targets/wee1/)
- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Dalpiciclib](https://onco.cc/drugs/dalpiciclib/), [Eprenetapopt](https://onco.cc/drugs/eprenetapopt/), [Palbociclib](https://onco.cc/drugs/palbociclib/), [Ribociclib](https://onco.cc/drugs/ribociclib/)
- key papers: [Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018/), [Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer](https://onco.cc/key-papers/paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018/), [Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers](https://onco.cc/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/), [Comprehensive genomic characterization of squamous cell lung cancers](https://onco.cc/key-papers/paper-tcga-lung-squamous-nature-2012/), [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [Comprehensive molecular portraits of human breast tumours](https://onco.cc/key-papers/paper-tcga-breast-molecular-portraits-nature-2012/), [El-Deiry 1993: WAF1, the gene through which p53 stops cell division](https://onco.cc/key-papers/paper-el-deiry-waf1-p21-cell-1993/), [Genomic correlates of clinical outcome in advanced prostate cancer](https://onco.cc/key-papers/paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019/), [Genomics of lethal prostate cancer at diagnosis and castration resistance](https://onco.cc/key-papers/paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020/), [Levine 1997: p53, the cellular gatekeeper for growth and division](https://onco.cc/key-papers/paper-levine-p53-gatekeeper-cell-1997/), [Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer](https://onco.cc/key-papers/paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase](https://onco.cc/key-papers/paper-sherr-roberts-cdk-inhibitors-genesdev-1999/), [The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas](https://onco.cc/key-papers/paper-herschkowitz-rb1-loss-basal-like-bcr-2008/), [Vogelstein, Lane and Levine 2000: surfing the p53 network](https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)
- companies: [Bulsara Bioworks](https://onco.cc/companies/bulsara-bioworks/), [Circle Pharma](https://onco.cc/companies/circle-pharma/)
- pairings: [CDK4/6 inhibitor + endocrine therapy](https://onco.cc/pairings/cdk46-plus-endocrine/)
- people: [Bruce W. Stillman](https://onco.cc/people/bruce-stillman/), [Paul Nurse](https://onco.cc/people/paul-nurse/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- ideas: [An open-science consortium on the undruggable drivers, open until a candidate](https://onco.cc/ideas/idea-fund-precompetitive-undruggable-consortium/), [Degrade the damaged p53 protein rather than trying to repair it](https://onco.cc/ideas/idea-bio1-mutant-p53-degrader/), [Extend p53 reactivation beyond the Y220C mutation](https://onco.cc/ideas/idea-bio1-p53-mutant-reactivator-expansion/), [Milestone prizes for first-in-class mechanisms reaching human proof of concept](https://onco.cc/ideas/idea-fund-first-in-class-prize/)
- pathways: [Basal cell carcinoma (KEGG map)](https://onco.cc/pathways/basal-cell-carcinoma-signalling/), [Bladder cancer (KEGG map)](https://onco.cc/pathways/bladder-cancer-signalling/), [Breast cancer (KEGG map)](https://onco.cc/pathways/breast-cancer-signalling/), [Cellular senescence](https://onco.cc/pathways/senescence/), [Chemical carcinogenesis - receptor activation](https://onco.cc/pathways/chemical-carcinogenesis-receptor-activation/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Chronic myeloid leukaemia (KEGG map)](https://onco.cc/pathways/cml-signalling/), [Circadian control](https://onco.cc/pathways/circadian-control/), [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [DNA replication stress](https://onco.cc/pathways/replication-stress/), [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Endometrial cancer (KEGG map)](https://onco.cc/pathways/endometrial-cancer-signalling/), [Gastric cancer (KEGG map)](https://onco.cc/pathways/gastric-cancer-signalling/), [Glioma (KEGG map)](https://onco.cc/pathways/glioma-signalling/), [Hepatocellular carcinoma (KEGG map)](https://onco.cc/pathways/hepatocellular-carcinoma-signalling/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Melanoma (KEGG map)](https://onco.cc/pathways/melanoma-signalling/), [MicroRNAs in cancer](https://onco.cc/pathways/micrornas-in-cancer/), [Mitosis & the spindle assembly checkpoint](https://onco.cc/pathways/mitotic-spindle-checkpoint/), [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Oncogenic viruses](https://onco.cc/pathways/oncogenic-viruses/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [Prostate cancer (KEGG map)](https://onco.cc/pathways/prostate-cancer-signalling/), [Small cell lung cancer (KEGG map)](https://onco.cc/pathways/sclc-signalling/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/), [Thyroid cancer (KEGG map)](https://onco.cc/pathways/thyroid-cancer-signalling/)
- terms: [Apoptosis](https://onco.cc/terms/apoptosis/), [Cell cycle](https://onco.cc/terms/cell-cycle/), [Checkpoint (two meanings)](https://onco.cc/terms/checkpoint/), [Hallmark: evading growth suppressors](https://onco.cc/terms/evading-growth-suppressors/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Tumour suppressor gene](https://onco.cc/terms/tumour-suppressor-gene/), [Whole-genome doubling (WGD)](https://onco.cc/terms/whole-genome-doubling/)

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JSON: https://onco.cc/api/v1/entities/p53-cell-cycle.json