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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 9 products (5 approved), 94 trials, 13 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.
Phosphorylate RB to release E2F and drive G1-S transition; cyclin D1 amplification and RB loss modulate sensitivity.
| 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.
| Modality | Approved | Phase 3 | Phase 2 |
|---|---|---|---|
| Small molecule 9 |
| Trial | 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). | |
PATINA NCT02947685 | 3 | Positive | Hormone receptor-positive, HER2-positive metastatic breast cancer after induction chemotherapy with anti-HER2 therapy: maintenance anti-HER2 therapy and endocrine therapy with or without palbociclib | Palbociclib added to maintenance anti-HER2 and endocrine therapy lengthened progression-free survival. | |
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. | |
NATALEE NCT03701334 | 3 | Positive | Adjuvant ribociclib 3 years + endocrine therapy in stage II-III HR+/HER2- breast cancer | iDFS HR 0.75. | |
DAWNA-1 NCT03927456 | 3 | Positive | HR-positive, HER2-negative advanced breast cancer after progression on endocrine therapy, China: dalpiciclib or placebo plus fulvestrant | PFS 15.7 vs 7.2 months, HR 0.42. | |
PENELOPE-B NCT01864746 | 3 | Negative | Hormone receptor-positive, HER2-negative early breast cancer with residual disease and high risk of relapse after neoadjuvant chemotherapy: one year of palbociclib or placebo added to endocrine therapy | One year of palbociclib added to endocrine therapy did not improve invasive disease-free survival. | |
| 3 | Active | A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI (Anastrozole or Letrozole) Plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or Plus Placebo, and to Compare Fulvestrant Plus Abemaciclib or Plus Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer | - | ||
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. | |
| 3 | Active | MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer | - | ||
| 3 | Active | JUNIPER: A Randomized Phase 3 Study of Abemaciclib Plus Best Supportive Care Versus Erlotinib Plus Best Supportive Care in Patients With Stage IV NSCLC With a Detectable KRAS Mutation Who Have Progressed After Platinum-Based Chemotherapy | - | ||
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). | |
| 3 | Active | SERENA-4: A Randomised, Multicentre, Double-Blind, Phase III Study of AZD9833 (an Oral SERD) Plus Palbociclib Versus Anastrozole Plus Palbociclib for the Treatment of Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer Who Have Not Received Any Systemic Treatment for Advanced Disease | - | ||
| 3 | Recruiting | SERAFA-1: A Single Arm, Open Label, Multicentre, Phase IIIb Study Of Camizestrant Plus Ribociclib in 1st Line Treatment of ER Positive, HER2-negative Advanced Breast Cancer Patients | - | ||
| 3 | Active | CYCLONE 3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abemaciclib in Combination With Abiraterone Plus Prednisone in Men With High-Risk Metastatic Hormone-Sensitive Prostate Cancer | - | ||
| 3 | Recruiting | A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of GB491 in Combination With Letrozole in Subjects With HR Positive and HER2 Negative Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Received Systemic Therapy in This Disease Setting | - | ||
| 3 | Active | A Phase III Randomized, Open-Label Study Evaluating Efficacy and Safety of Giredestrant Compared With Fulvestrant, Both Combined With a CDK4/6 Inhibitor, in Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer With Resistance to Prior Adjuvant Endocrine Therapy | - | ||
| 3 | Active | A Phase Ib/III, Open-label, Randomised Study of Capivasertib Plus CDK4/6 Inhibitors and Fulvestrant Versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292) | - | ||
| 3 | Active | Randomized, Double-blind, Parallel-controlled Phase III Trial to Evaluate the Efficacy and Safety of TQB3616 Combined With Endocrine Therapy Versus Placebo Combined With Endocrine Therapy in Hormone Receptors (HR)-Positive and Human Epidermal GrowthFactor Receptor-2 (HER2) -Negative Breast Cancer Adjuvant Therapy | - | ||
| 3 | Recruiting | A Phase III, Randomised, Double-blind, Placebo-controlled, Multicentre Trial Comparing Efficacy and Safety of Trilaciclib Versus Placebo in Participants With Limited-stage Small Cell Lung Cancer | - | ||
| 3 | Recruiting | An Open Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of the Combination of Lasofoxifene and Abemaciclib to the Combination of Fulvestrant and Abemaciclib for the Treatment of Pre- and Postmenopausal Women and Men With Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation | - | ||
| 3 | Active | Phase 3, Open-Label, Randomized, Study Comparing Gedatolisib Combined With Fulvestrant & With or Without Palbociclib to Standard-of-Care Therapies in Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination w/Non-Steroidal Aromatase Inhibitor Therapy | - | ||
| 3 | Completed | Molecular Profiling of Advanced Soft-tissue Sarcomas. A Phase III Study | - | ||
| 3 | Recruiting | A Phase 3 Randomized, Double-Blind, Active-Controlled Study of Palazestrant With Ribociclib Versus Letrozole With Ribociclib for the First-Line Treatment of ER+, HER2- Advanced Breast Cancer (OPERA-02) | - | ||
| 3 | Recruiting | VIKTORIA-2: A Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Gedatolisib With Endocrine Therapy and Palbociclib vs Endocrine Therapy and Ribociclib as First-Line Treatment in Patients With HR-Positive and HER2-Negative Advanced Breast Cancer | - | ||
| 3 | Active | A Multicenter, Randomized, Double-blind Phase III Study：SHR6390/Placebo Combined With Endocrine Therapy for the Adjuvant Treatment of Hormone Receptor Positive,Human Epidermal Receptor 2 Negative, Node-positive, High Risk, Early Stage，Female Breast Cancer | - | ||
| 3 | Recruiting | A Phase IIIb Study to Characterize the Efficacy and Safety of Adjuvant Ribociclib Plus Endocrine Therapy in a Close-to-clinical Practice Patient Population With HR+ HER2- Early Breast Cancer (Adjuvant WIDER) | - |
Y537S/D538G render ER constitutively active; arise under aromatase-inhibitor pressure, detectable in ctDNA.
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
CCNE1 amplification or CDK2 activity bypasses the G1 block.
PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
KEGG's bladder cancer map shows two routes: low-grade papillary tumours driven by FGFR3 or HRAS activating the MAPK relay, and high-grade invasive tumours that lose TP53 and RB1. Erdafitinib targets the first route; antibody-drug conjugates and PD-1 antibodies now anchor treatment of the second.
Which nodes have drugs →KEGG's breast cancer map lays out the three clinical subtypes as signalling routes: oestrogen receptor driving cyclin D and CDK4/6 in hormone-receptor-positive disease, HER2 driving PI3K/AKT and MAPK in HER2-positive disease, and EGFR, Notch, Wnt and BRCA defects in triple-negative disease. Each route has its own drug class.
Which nodes have drugs →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 →Before a cell divides it must copy three billion letters of DNA exactly once, 'licensing' thousands of start points in advance and firing them in waves. Cancers driven by MYC, cyclin E or RAS fire excess start points too fast, and antimetabolites such as 5-FU, topoisomerase poisons such as irinotecan and platinum drugs all jam this copying machinery.
Which nodes have drugs →This KEGG map shows the two genetic roads to glioblastoma: primary tumours amplify EGFR and lose PTEN and p16, secondary tumours from lower-grade astrocytomas over-express PDGF and CDK4 and lose TP53 and RB. It explains why growth-factor and cell-cycle drugs are the main targeted options in brain tumours, and why paediatric low-grade gliomas with BRAF changes respond to MAPK inhibitors.
Which nodes have drugs →KEGG's melanoma map shows BRAF or NRAS mutations driving the MAPK growth relay, PTEN loss driving PI3K/AKT, and loss of the CDKN2A brakes (p16 and p14ARF) on CDK4/6 and p53. BRAF plus MEK inhibitors and immune checkpoint antibodies have transformed treatment.
Which nodes have drugs →KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Which nodes have drugs →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 →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 →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 →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →KEGG's small cell lung cancer map shows a tumour with both master brakes removed, RB1 and TP53, plus amplified MYC pushing the cell cycle and PTEN loss and BCL2 keeping cells alive. Chemotherapy with PD-L1 antibodies and the DLL3 T-cell engager tarlatamab are the current answers.
Which nodes have drugs →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 →| 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) |
No model entry for this target yet; check the cancer entries on the models page.
Why 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.
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.
The dossier as machine-readable JSON, at /api/v1/dossiers/cdk4-6.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-NC 4.0.