# The cell-cycle engine (cyclins & CDKs)

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

## TL;DR

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.

## Summary

Mitogens induce cyclin D, which with CDK4/6 mono-phosphorylates RB; cyclin E-CDK2 completes RB hyperphosphorylation, releasing E2F and committing the cell at the restriction point (the point of no return). Cyclin A-CDK2 drives S phase, cyclin A/B-CDK1 drive G2 and mitosis, with CDK1 activation controlled by WEE1/PKMYT1 (inhibitory phosphorylation) and CDC25 phosphatases. CDK7 (CAK) activates all CDKs and also drives transcription. INK4 proteins (p16 from CDKN2A) inhibit CDK4/6; CIP/KIP (p21, p27) inhibit CDK2; APC/C and SCF ubiquitin ligases destroy cyclins in order. Cancer alterations: CCND1 amplification, CDK4 amplification (liposarcoma), CDKN2A deletion (very common, also removes ARF), CCNE1 amplification (ovarian, gastric, endocrine-resistant breast), RB1 loss (SCLC, TNBC, resistant prostate). CDK4/6 inhibitors need intact RB; CCNE1 amplification and RB1 loss are the escape routes and the rationale for CDK2 inhibitors and CDK4-selective atirmociclib.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: 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).
- Interventions: CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) in HR+ breast cancer; CDK4-selective atirmociclib to spare neutrophils; CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease (trials); WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors force premature mitosis in CCNE1-amplified or TP53-mutant cells; CDK7 and CDK9 inhibitors hit transcription as well as the cycle

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cyclin-dependent_kinase
- Malumbres & Barbacid, Cell cycle, CDKs and cancer: a changing paradigm (Nat Rev Cancer 2009): https://doi.org/10.1038/nrc2602

## Connected records

- cancers: [Burkitt lymphoma](https://onco.cc/cancers/burkitt-lymphoma/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- technologies: [CDK4/6 inhibitors](https://onco.cc/technologies/cdk46-inhibitor/), [Endocrine therapy (SERMs, AIs, SERDs)](https://onco.cc/technologies/endocrine-therapy/)
- targets: [CCND3](https://onco.cc/targets/ccnd3/), [CDK4/6](https://onco.cc/targets/cdk4-6/), [CDKN1A](https://onco.cc/targets/cdkn1a/), [CDKN2A](https://onco.cc/targets/cdkn2a/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/), [ID3](https://onco.cc/targets/id3/), [MYC](https://onco.cc/targets/myc-gene/), [TCF3](https://onco.cc/targets/tcf3/), [TP53](https://onco.cc/targets/tp53/), [WEE1](https://onco.cc/targets/wee1/)
- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Atirmociclib](https://onco.cc/drugs/atirmociclib/), [Palbociclib](https://onco.cc/drugs/palbociclib/), [Ribociclib](https://onco.cc/drugs/ribociclib/)
- pathways: [Bladder cancer (KEGG map)](https://onco.cc/pathways/bladder-cancer-signalling/), [Breast cancer (KEGG map)](https://onco.cc/pathways/breast-cancer-signalling/), [DNA replication & origin licensing](https://onco.cc/pathways/dna-replication-licensing/), [DNA replication stress](https://onco.cc/pathways/replication-stress/), [Melanoma (KEGG map)](https://onco.cc/pathways/melanoma-signalling/), [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/), [Oestrogen receptor signalling](https://onco.cc/pathways/er-signaling/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [Small cell lung cancer (KEGG map)](https://onco.cc/pathways/sclc-signalling/)
- terms: [Aneuploidy and chromosomal instability as the cause of cancer](https://onco.cc/terms/aneuploidy-theory-of-cancer/), [Endocrine resistance](https://onco.cc/terms/endocrine-resistance/), [Hallmark: evading growth suppressors](https://onco.cc/terms/evading-growth-suppressors/), [t(11;14), cyclin D1 and SOX11](https://onco.cc/terms/cyclin-d1-t11-14/)
- key papers: [Cell cycle, CDKs and cancer: a changing paradigm](https://onco.cc/key-papers/paper-malumbres-nat-rev-cancer/), [El-Deiry 1993: WAF1, the gene through which p53 stops cell division](https://onco.cc/key-papers/paper-el-deiry-waf1-p21-cell-1993/), [MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition](https://onco.cc/key-papers/paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012/), [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/), [Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase](https://onco.cc/key-papers/paper-sherr-roberts-cdk-inhibitors-genesdev-1999/)

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