{"entity":{"id":"cdk4-6","kind":"target","name":"CDK4/6","aka":[],"tldr":"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.","summary":"CDK4 and CDK6 phosphorylate RB to release E2F and drive the G1 to S transition, so inhibiting them halts cell-cycle entry in tumours that still have functional RB. Palbociclib, ribociclib and abemaciclib with endocrine therapy are first-line standard in HR-positive HER2-negative advanced breast cancer, roughly doubling the time the disease stays controlled, and ribociclib (NATALEE) and abemaciclib (monarchE) are approved as adjuvant therapy. Cyclin D1 (CCND1) amplification occurs in 15 to 20 percent of HR-positive breast cancers but the drugs work regardless of it, and CDK4 amplification is near-universal in well- and dedifferentiated liposarcoma. Resistance through RB loss, CDK2 activation and cyclin E amplification is common, and CDK4-selective and CDK2 inhibitors are being developed to address it. CDK4/6 is the engine of cell division that hormone therapy alone could not stop.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_4","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_4"}],"tags":["kinase"],"related":[],"cancers":["breast-hr-positive","sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["tqb3616"],"companies":[],"institutions":[],"pathways":["p53-cell-cycle","er-signaling","bladder-cancer-signalling","breast-cancer-signalling","glioma-signalling","melanoma-signalling","nsclc-signalling","pancreatic-cancer-signalling","sclc-signalling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"CDK4, CDK6","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"Broadly expressed or essential: HPA lists CDK4 among essential proteins and finds the RNA at low tissue specificity; the 9 medicines aimed at it (TQB3616, Abemaciclib, Atirmociclib and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA CDK4: RNA low tissue specificity; high antibody staining in 6 normal tissues; highest cancer staining cervical cancer (6 of 12 high). HPA CDK6: RNA tissue enhanced (lymphoid tissue 38 nTPM); high antibody staining in 4 normal tissues; highest cancer staining head and neck cancer (2 of 4 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Breast cancer (all types), Sarcomas (soft tissue, bone, GIST)); approvals of single-target medicines aimed at it also list Lung cancer (all types), not counted; Open Targets associates it with 5 specific cancer types at or above 0.5 (melanoma, cutaneous malignant, susceptibility to, 3, breast carcinoma, breast cancer, small cell lung carcinoma, familial melanoma). (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas CDK4 tissue","url":"https://www.proteinatlas.org/ENSG00000135446-CDK4/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas CDK6 tissue","url":"https://www.proteinatlas.org/ENSG00000105810-CDK6/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000135446 associations","url":"https://platform.opentargets.org/target/ENSG00000135446/associations","note":"cancer associations at or above 0.5 (CC0)"},{"label":"Open Targets ENSG00000105810 associations","url":"https://platform.opentargets.org/target/ENSG00000105810/associations","note":"cancer associations at or above 0.5 (CC0)"}],"biology":"Phosphorylate RB to release E2F and drive G1-S transition; cyclin D1 amplification and RB loss modulate sensitivity.","whereFound":["HR+ breast cancer","Liposarcoma (CDK4 amplification)","Mantle cell lymphoma"],"targetClass":"kinase","prevalence":[{"cancerId":"breast-hr-positive","pct":"15-20","measure":"Cyclin D1 (CCND1) amplification","source":"https://www.cbioportal.org/study/summary?id=brca_tcga_pan_can_atlas_2018","note":"Inhibitors work regardless of amplification"},{"cancerId":"sarcoma","pct":">90","measure":"Well-/dedifferentiated liposarcoma CDK4 amplification","source":"https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_4"}]},"route":"/targets/cdk4-6/","neighbours":{"cancer":[{"id":"ependymoma","kind":"cancer","name":"Ependymoma","route":"/cancers/ependymoma/"},{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"male-breast-cancer","kind":"cancer","name":"Male breast cancer","route":"/cancers/male-breast-cancer/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"rhabdomyosarcoma","kind":"cancer","name":"Rhabdomyosarcoma","route":"/cancers/rhabdomyosarcoma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"drug":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"atirmociclib","kind":"drug","name":"Atirmociclib","route":"/drugs/atirmociclib/"},{"id":"avzo-023","kind":"drug","name":"AVZO-023","route":"/drugs/avzo-023/"},{"id":"dalpiciclib","kind":"drug","name":"Dalpiciclib","route":"/drugs/dalpiciclib/"},{"id":"lerociclib","kind":"drug","name":"Lerociclib","route":"/drugs/lerociclib/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"},{"id":"tqb3616","kind":"drug","name":"TQB3616","route":"/drugs/tqb3616/"},{"id":"trilaciclib","kind":"drug","name":"Trilaciclib","route":"/drugs/trilaciclib/"}],"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":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"dna-replication-licensing","kind":"pathway","name":"DNA replication & origin licensing","route":"/pathways/dna-replication-licensing/"},{"id":"glioma-signalling","kind":"pathway","name":"Glioma (KEGG map)","route":"/pathways/glioma-signalling/"},{"id":"melanoma-signalling","kind":"pathway","name":"Melanoma (KEGG map)","route":"/pathways/melanoma-signalling/"},{"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":"oncogenic-viruses","kind":"pathway","name":"Oncogenic viruses","route":"/pathways/oncogenic-viruses/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"}],"trial":[{"id":"dawna-1","kind":"trial","name":"DAWNA-1","route":"/trials/dawna-1/"},{"id":"ember-3","kind":"trial","name":"EMBER-3","route":"/trials/ember-3/"},{"id":"fourlight-1","kind":"trial","name":"FOURLIGHT-1","route":"/trials/fourlight-1/"},{"id":"inavo120","kind":"trial","name":"INAVO120","route":"/trials/inavo120/"},{"id":"monaleesa-2","kind":"trial","name":"MONALEESA-2","route":"/trials/monaleesa-2/"},{"id":"monarch-3","kind":"trial","name":"MONARCH 3","route":"/trials/monarch-3/"},{"id":"pallas-penelope-b","kind":"trial","name":"PALLAS & PENELOPE-B","route":"/trials/pallas-penelope-b/"},{"id":"paloma-2","kind":"trial","name":"PALOMA-2","route":"/trials/paloma-2/"},{"id":"postmonarch","kind":"trial","name":"postMONARCH","route":"/trials/postmonarch/"},{"id":"zen-3694-abemaciclib-nut","kind":"trial","name":"ZEN-3694 with abemaciclib in NUT carcinoma, breast cancer and other solid tumours (NCI phase 1)","route":"/trials/zen-3694-abemaciclib-nut/"}],"term":[{"id":"cdkn2a-homozygous-deletion","kind":"term","name":"CDKN2A/B homozygous deletion","route":"/terms/cdkn2a-homozygous-deletion/"},{"id":"cell-cycle","kind":"term","name":"Cell cycle","route":"/terms/cell-cycle/"},{"id":"checkpoint","kind":"term","name":"Checkpoint (two meanings)","route":"/terms/checkpoint/"},{"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":"hormone-therapy","kind":"term","name":"Hormone therapy","route":"/terms/hormone-therapy/"},{"id":"kinase","kind":"term","name":"Kinase","route":"/terms/kinase/"},{"id":"cyclin-d1-t11-14","kind":"term","name":"t(11;14), cyclin D1 and SOX11","route":"/terms/cyclin-d1-t11-14/"}],"idea":[{"id":"idea-ecdna-targeting","kind":"idea","name":"Attack extrachromosomal DNA, the engine of oncogene amplification","route":"/ideas/idea-ecdna-targeting/"},{"id":"idea-cdk4-selective-first-line","kind":"idea","name":"CDK4-selective inhibitors as the new first-line backbone","route":"/ideas/idea-cdk4-selective-first-line/"}],"paper":[{"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-monarche-jco-2020","kind":"paper","name":"monarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancer","route":"/key-papers/paper-monarche-jco-2020/"},{"id":"paper-natalee-nejm-2024","kind":"paper","name":"NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer","route":"/key-papers/paper-natalee-nejm-2024/"},{"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/"},{"id":"paper-herschkowitz-rb1-loss-basal-like-bcr-2008","kind":"paper","name":"The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas","route":"/key-papers/paper-herschkowitz-rb1-loss-basal-like-bcr-2008/"}],"technology":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"company":[{"id":"circle-pharma","kind":"company","name":"Circle Pharma","route":"/companies/circle-pharma/"},{"id":"g1-therapeutics","kind":"company","name":"G1 Therapeutics","route":"/companies/g1-therapeutics/"},{"id":"kymera","kind":"company","name":"Kymera Therapeutics","route":"/companies/kymera/"}],"person":[{"id":"angela-demichele","kind":"person","name":"Angela DeMichele","route":"/people/angela-demichele/"},{"id":"debu-tripathy","kind":"person","name":"Debu Tripathy","route":"/people/debu-tripathy/"},{"id":"dennis-slamon","kind":"person","name":"Dennis J. Slamon","route":"/people/dennis-slamon/"},{"id":"gabriel-hortobagyi","kind":"person","name":"Gabriel N. Hortobagyi","route":"/people/gabriel-hortobagyi/"},{"id":"giulio-draetta","kind":"person","name":"Giulio Draetta","route":"/people/giulio-draetta/"},{"id":"massimo-cristofanilli","kind":"person","name":"Massimo Cristofanilli","route":"/people/massimo-cristofanilli/"},{"id":"matthew-goetz","kind":"person","name":"Matthew P. Goetz","route":"/people/matthew-goetz/"},{"id":"paul-nurse","kind":"person","name":"Paul Nurse","route":"/people/paul-nurse/"},{"id":"richard-finn","kind":"person","name":"Richard S. Finn","route":"/people/richard-finn/"},{"id":"im-seock-ah","kind":"person","name":"Seock-Ah Im","route":"/people/im-seock-ah/"},{"id":"stephen-johnston","kind":"person","name":"Stephen Johnston","route":"/people/stephen-johnston/"},{"id":"park-yeon-hee","kind":"person","name":"Yeon Hee Park","route":"/people/park-yeon-hee/"}],"institution":[{"id":"instituto-alexander-fleming","kind":"institution","name":"Instituto Alexander Fleming","route":"/institutions/instituto-alexander-fleming/"}]}}