{"entity":{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","aka":[],"tldr":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Cyclin-dependent_kinase","links":[{"label":"Malumbres & Barbacid, Cell cycle, CDKs and cancer: a changing paradigm (Nat Rev Cancer 2009)","url":"https://doi.org/10.1038/nrc2602"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["breast-hr-positive","sarcoma","ovarian","sclc","gallbladder"],"sections":[],"technologies":["cdk46-inhibitor","endocrine-therapy"],"targets":["cdk4-6","wee1","estrogen-receptor","tp53"],"drugs":["palbociclib","ribociclib","abemaciclib","atirmociclib"],"companies":[],"institutions":[],"pathways":["p53-cell-cycle","er-signaling","replication-stress","mitotic-spindle-checkpoint"],"terms":["endocrine-resistance","evading-growth-suppressors"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-malumbres-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"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).","nodes":[{"id":"mit","label":"Mitogens (ER, RTK, RAS)","x":12,"y":12,"targetId":"estrogen-receptor"},{"id":"d46","label":"Cyclin D-CDK4/6","x":12,"y":42,"targetId":"cdk4-6"},{"id":"p16","label":"p16 (CDKN2A)","x":12,"y":75},{"id":"rb","label":"RB → E2F released","x":40,"y":42},{"id":"e2","label":"Cyclin E-CDK2","x":40,"y":72},{"id":"p21","label":"p21 / p27","x":40,"y":12,"targetId":"tp53"},{"id":"s","label":"S phase (cyclin A)","x":68,"y":72},{"id":"b1","label":"Cyclin B-CDK1","x":68,"y":42},{"id":"wee1","label":"WEE1 / PKMYT1","x":90,"y":20,"targetId":"wee1"},{"id":"m","label":"Mitosis","x":90,"y":72}],"edges":[{"from":"mit","to":"d46","type":"activates"},{"from":"p16","to":"d46","type":"inhibits"},{"from":"d46","to":"rb","type":"activates"},{"from":"p21","to":"e2","type":"inhibits"},{"from":"rb","to":"e2","type":"activates"},{"from":"e2","to":"rb","type":"activates"},{"from":"e2","to":"s","type":"activates"},{"from":"s","to":"b1","type":"activates"},{"from":"wee1","to":"b1","type":"inhibits"},{"from":"b1","to":"m","type":"activates"}],"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"]},"route":"/pathways/cell-cycle-engine-cdks/","neighbours":{"cancer":[{"id":"burkitt-lymphoma","kind":"cancer","name":"Burkitt lymphoma","route":"/cancers/burkitt-lymphoma/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}],"target":[{"id":"ccnd3","kind":"target","name":"CCND3","route":"/targets/ccnd3/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"cdkn1a","kind":"target","name":"CDKN1A","route":"/targets/cdkn1a/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"id3","kind":"target","name":"ID3","route":"/targets/id3/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"tcf3","kind":"target","name":"TCF3","route":"/targets/tcf3/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"}],"drug":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"atirmociclib","kind":"drug","name":"Atirmociclib","route":"/drugs/atirmociclib/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"}],"pathway":[{"id":"bladder-cancer-signalling","kind":"pathway","name":"Bladder cancer (KEGG map)","route":"/pathways/bladder-cancer-signalling/"},{"id":"breast-cancer-signalling","kind":"pathway","name":"Breast cancer (KEGG map)","route":"/pathways/breast-cancer-signalling/"},{"id":"dna-replication-licensing","kind":"pathway","name":"DNA replication & origin licensing","route":"/pathways/dna-replication-licensing/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"melanoma-signalling","kind":"pathway","name":"Melanoma (KEGG map)","route":"/pathways/melanoma-signalling/"},{"id":"mitotic-spindle-checkpoint","kind":"pathway","name":"Mitosis & the spindle assembly checkpoint","route":"/pathways/mitotic-spindle-checkpoint/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"er-signaling","kind":"pathway","name":"Oestrogen receptor signalling","route":"/pathways/er-signaling/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"}],"term":[{"id":"aneuploidy-theory-of-cancer","kind":"term","name":"Aneuploidy and chromosomal instability as the cause of cancer","route":"/terms/aneuploidy-theory-of-cancer/"},{"id":"endocrine-resistance","kind":"term","name":"Endocrine resistance","route":"/terms/endocrine-resistance/"},{"id":"evading-growth-suppressors","kind":"term","name":"Hallmark: evading growth suppressors","route":"/terms/evading-growth-suppressors/"},{"id":"cyclin-d1-t11-14","kind":"term","name":"t(11;14), cyclin D1 and SOX11","route":"/terms/cyclin-d1-t11-14/"}],"paper":[{"id":"paper-malumbres-nat-rev-cancer","kind":"paper","name":"Cell cycle, CDKs and cancer: a changing paradigm","route":"/key-papers/paper-malumbres-nat-rev-cancer/"},{"id":"paper-el-deiry-waf1-p21-cell-1993","kind":"paper","name":"El-Deiry 1993: WAF1, the gene through which p53 stops cell division","route":"/key-papers/paper-el-deiry-waf1-p21-cell-1993/"},{"id":"paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012","kind":"paper","name":"MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition","route":"/key-papers/paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012/"},{"id":"paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020","kind":"paper","name":"Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer","route":"/key-papers/paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020/"},{"id":"paper-sherr-roberts-cdk-inhibitors-genesdev-1999","kind":"paper","name":"Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase","route":"/key-papers/paper-sherr-roberts-cdk-inhibitors-genesdev-1999/"}]}}