CDK4/6
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. This dossier gathers the 4 products (3 approved), 11 trials, 6 pathways and 4 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Phosphorylate RB to release E2F and drive G1-S transition; cyclin D1 amplification and RB loss modulate sensitivity.
- HR+ breast cancer
- Liposarcoma (CDK4 amplification)
- Mantle cell lymphoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| 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.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 4 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| persevERA NCT04546009 | 3 | Negative | First-line ER+/HER2- advanced breast cancer: giredestrant + palbociclib vs letrozole + palbociclib | PFS 33.1 vs 28.2 months, not significant. | |
| EMBER-3 NCT04975308 | 3 | Positive | ER+/HER2- advanced breast cancer after ≥1 endocrine line: imlunestrant vs standard endocrine therapy, and imlunestrant + abemaciclib vs imlunestrant | PFS HR 0.62 (ESR1-mutant, monotherapy); HR 0.57 (combination vs monotherapy). | |
| postMONARCH NCT05169567 | 3 | Positive | HR+/HER2- advanced breast cancer after progression on CDK4/6 + endocrine therapy: abemaciclib + fulvestrant vs placebo + fulvestrant | PFS 6.0 vs 5.3 months, HR 0.73. | |
| INAVO120 NCT04191499 | 3 | Positive | First-line PIK3CA-mutant HR+/HER2- advanced breast cancer relapsing on/after adjuvant endocrine therapy: inavolisib + palbociclib + fulvestrant vs placebo + palbociclib + fulvestrant | PFS 15.0 vs 7.3 months, HR 0.43; OS 34.0 vs 27.0 months, HR 0.67. | |
| NATALEE NCT03701334 | 3 | Positive | Adjuvant ribociclib 3 years + endocrine therapy in stage II-III HR+/HER2- breast cancer | iDFS HR 0.75. | |
| monarchE NCT03155997 | 3 | Positive | Adjuvant abemaciclib 2 years + endocrine therapy in high-risk node-positive HR+/HER2- breast cancer | iDFS HR 0.68. | |
| PALLAS & PENELOPE-B NCT02513394 | 3 | Negative | Adjuvant palbociclib + endocrine therapy in HR+/HER2- early breast cancer (PALLAS, 2 years; PENELOPE-B, 1 year after residual disease) | PALLAS iDFS HR 0.96; PENELOPE-B iDFS HR 0.93; both null. | |
| MONARCH 3 NCT02246621 | 3 | Positive | First-line postmenopausal HR+/HER2- advanced breast cancer: abemaciclib + NSAI vs placebo + NSAI | PFS HR 0.54; OS 66.8 vs 53.7 months, HR 0.80 (NS). | |
| MONALEESA-2 NCT01958021 | 3 | Positive | First-line postmenopausal HR+/HER2- advanced breast cancer: ribociclib + letrozole vs placebo + letrozole | OS 63.9 vs 51.4 months, HR 0.76. | |
| PALOMA-2 NCT01740427 | 3 | Mixed | First-line postmenopausal HR+/HER2- advanced breast cancer: palbociclib + letrozole vs placebo + letrozole | PFS HR 0.56; OS HR 0.96 (NS). | |
| FOURLIGHT-1 NCT06105632 | 2 | Positive | HR+/HER2- advanced breast cancer after CDK4/6 inhibitor: atirmociclib + fulvestrant vs fulvestrant | PFS improved (HR not yet published in detail). |
Resistance routes that involve this target
Unaddressed routes →Y537S/D538G render ER constitutively active; arise under aromatase-inhibitor pressure, detectable in ctDNA.
- Oral SERDs (elacestrant, imlunestrant, camizestrant) and PROTAC vepdegestrant; ctDNA-guided early switch (SERENA-6)
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
- Switch to chemotherapy or ADCs (T-DXd for HER2-low, sacituzumab, Dato-DXd)
CCNE1 amplification or CDK2 activity bypasses the G1 block.
- CDK2 inhibitors (AVZO-021 and others) and CDK4-selective inhibitors in trials
PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
- Capivasertib, inavolisib, alpelisib, everolimus, gedatolisib by genotype
Pathways where it is a node
Pathway-to-drug matrix →- Cellular senescenceNode: p16 → RB · 2 druggable nodes
Damaged cells can stop dividing permanently instead of dying. That protects against cancer at first, but senescent cells linger, secrete inflammatory signals, and after chemotherapy can help tumours relapse, so removing them (senolytics) is a new strategy.
Which nodes have drugs → - DNA replication & origin licensingNode: CDK2 / DDK firing · 3 druggable nodes
Before a cell divides it must copy three billion letters of DNA exactly once. It does this by 'licensing' thousands of start points in advance and then firing them in waves. Cancers fire too many too fast, and many chemotherapies work by starving or jamming the copying machinery.
Which nodes have drugs → - Oestrogen receptor signallingNode: CDK4/6 · 2 druggable nodes
In hormone-positive breast cancer, oestrogen binds its receptor, which switches on genes that make the cell divide. Every endocrine therapy cuts this chain somewhere.
Which nodes have drugs → - Oncogenic virusesNode: RB inactivated · 3 druggable nodes
About one cancer in eight worldwide is caused by a virus. HPV, hepatitis B and C, Epstein-Barr, HTLV-1, KSHV and Merkel cell polyomavirus each hijack the same brakes cancer normally has to mutate, which is why vaccines against HPV and HBV are among the most effective anti-cancer drugs ever made.
Which nodes have drugs → - p53 / RB / cell-cycle checkpointNode: CDK4/6 – cyclin D · 4 druggable nodes
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.
Which nodes have drugs → - The cell-cycle engine (cyclins & CDKs)Node: Cyclin D – CDK4/6 · 4 druggable nodes
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.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| Ki-67 IHC (MIB-1) Multiple (Agilent, Roche, Leica) · FDA CDx 2021 | IHC | At least 20% (monarchE high-risk cohort; the abemaciclib label's Ki-67 requirement was removed in 2023) |
Preclinical models
All models →No model entry for this target yet; check the cancer entries on the models page.
Open questions
All open questions →- 01
After progression on a CDK4/6 inhibitor, does continuing CDK4/6 inhibition with a new endocrine partner beat switching to a targeted or antibody-drug conjugate approach?
clinicalclinicWhy unresolved. postMONARCH showed modest benefit from continuing abemaciclib; resistance runs through RB1 loss, cyclin E and PI3K activation, and genotype-directed options (capivasertib, inavolisib, oral SERDs) compete for the same slot.
What would answer it. Genotype-stratified randomised trials at CDK4/6 progression comparing continuation, PI3K/AKT-directed therapy, oral SERDs and ADCs.
Source: postMONARCH (ClinicalTrials.gov)
Ideas and companies
Key papers and the live literature
Preprints →- NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer · New England Journal of Medicine 2024
- monarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancer · Journal of Clinical Oncology 2020
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.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/cdk4-6.json. Licence CC BY 4.0.