Loading
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.
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.
In plain words · 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.
Backbone ribbon from PDB 5L2I. RCSB PDB 5L2I. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Backbone ribbon with the bound drug in ball-and-stick (pink carbons). The wireframe view adds the pocket residues within 5 Å as a thin cage.
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.
Phosphorylate RB to release E2F and drive G1-S transition; cyclin D1 amplification and RB loss modulate sensitivity.
9 products aim at CDK4/6: small molecules. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
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.)
Sources: Human Protein Atlas CDK4 tissue; Human Protein Atlas CDK6 tissue; Open Targets ENSG00000135446 associations; Open Targets ENSG00000105810 associations
Phosphorylate RB to release E2F and drive G1-S transition; cyclin D1 amplification and RB loss modulate sensitivity.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Duodenum, Endometrium, Heart muscle, Small intestine, Soft tissue.
RNA cancer enriched: Glioblastoma Multiforme 998 pTPM.
Medium only: carcinoid, glioma, pancreatic cancer, prostate cancer.
HPA CDK4 tissue · HPA CDK4 pathology · HPA protein class: Essential proteins, FDA approved drug targets
RNA: tissue enhanced (lymphoid tissue 38 nTPM), detected in many normal tissues.
Medium: Appendix, Bone marrow, Breast, Gallbladder, Kidney, Lung, Lymph node, Parathyroid gland.
Medium only: colorectal cancer, lung cancer, melanoma, prostate cancer.
HPA CDK6 tissue · HPA CDK6 pathology · HPA protein class: FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Sarcomas | >90% | Well-/dedifferentiated liposarcoma CDK4 amplification | Wikipedia | |
| HR-positive / HER2-negative breast cancer | 15-20% | Cyclin D1 (CCND1) amplification | Inhibitors work regardless of amplification | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Abemaciclib was the first CDK4/6 inhibitor approved after surgery for high-risk hormone-positive breast cancer.
A next-generation pill that blocks only CDK4, not CDK6, to keep the benefit of today's drugs without the low blood counts.
AVZO-023 is a small-molecule inhibitor from Avenzo Therapeutics, Inc., in registered phase 2 trials for metastatic cancer.
Dalpiciclib is Hengrui's CDK4/6 inhibitor, the first China-developed drug of the class, approved for hormone-driven advanced breast cancer on the DAWNA trials.
Lerociclib is a CDK4/6 inhibitor from G1 Therapeutics developed in China by Genor Biopharma, in a phase 3 trial with letrozole for hormone receptor-positive breast cancer.
Palbociclib was the first CDK4/6 inhibitor (2015), and in 2026 became the first approved as maintenance in HER2-positive, hormone-positive breast cancer.
Ribociclib is the CDK4/6 inhibitor with the most consistent survival benefit, approved for a broad population of early breast cancer patients since 2024.
TQB3616 is an experimental small-molecule drug from Chia Tai Tianqing Pharmaceutical in phase 3 trials for HR-positive / HER2-negative breast cancer, aimed at CDK4/6.
Trilaciclib is given as an infusion just before chemotherapy for small cell lung cancer to put the bone marrow's stem cells briefly to sleep, so fewer are killed and patients need fewer transfusions and growth factor injections.
Ribociclib is a second adjuvant CDK4/6 option, and the only one with data in node-negative stage II disease. Roughly 3 in 100 patients avoid a relapse or death at three years, so the decision depends heavily on individual risk, tolerance of a three-year oral drug, and cost. Whether the benefit persists after treatment ends, as it did with abemaciclib, needs longer follow-up.
Women with hormone-receptor-positive, HER2-negative breast cancer that has spread to lymph nodes and has other high-risk features can now be offered two years of abemaciclib alongside their hormone therapy, with a durable reduction in relapse. It does not apply to node-negative or low-risk disease, and the diarrhoea and cost are real trade-offs to discuss.
Functional RB1 loss is part of basal-like biology, which explains why CDK4/6 inhibitors have not worked in TNBC and why the cell-cycle vulnerability there lies downstream of RB.
This review is the textbook basis for the cyclin D-CDK4/6-RB axis that palbociclib, ribociclib and abemaciclib target in breast cancer, and for reading CDKN2A loss and cyclin D1 amplification in tumour genomes.
This paper closed the loop between DNA damage, p53 and the cell cycle machinery. p21 is now a standard marker of p53 activity, part of how chemotherapy and radiotherapy stop cells dividing, and a component of the senescence response that CDK4/6 inhibitors exploit.
Query for this target: (TITLE:"CDK4/6" OR ABSTRACT:"CDK4/6" OR TITLE:"CDK4" OR ABSTRACT:"CDK4" OR TITLE:"CDK6" OR ABSTRACT:"CDK6") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about CDK4/6, not a curated reading list.
Shares Hallmark: evading growth suppressors, Melanoma (KEGG map), Small cell lung cancer (KEGG map), Non-small cell lung cancer (KEGG map) and the tag kinase.
Shares Melanoma (KEGG map), Bladder cancer (KEGG map), Breast cancer (KEGG map), Non-small cell lung cancer (KEGG map) and the tag kinase.
Shares Sarcomas (soft tissue, bone, GIST), HR-positive / HER2-negative breast cancer and the tag kinase.
Shares Mantle cell lymphoma and the tag kinase.
Shares Endocrine resistance, INAVO120, Glioma (KEGG map), Oestrogen receptor signalling and the tag kinase.
Shares Kinase, Melanoma (KEGG map), Glioma (KEGG map), Pancreatic cancer (KEGG map) and the tag kinase.
Shares Attack extrachromosomal DNA, the engine of oncogene amplification, Kinase, Glioma (KEGG map), Breast cancer (KEGG map) and the tag kinase.
Shares Kinase, Non-small cell lung cancer (KEGG map), Small-molecule kinase inhibitors and the tag kinase.