CDK4

Overview

CDK4 encodes a cyclin-dependent kinase central to G1/S cell-cycle progression; focal amplification deregulates the RB pathway and is therapeutically targeted by CDK4/6 inhibitors.

Alterations observed in the corpus

  • Focal CDK4 amplifications were among the most common genomic events in alveolar rhabdomyosarcoma (ARMS) in the 61-patient MSKCC extremity RMS cohort, with frequencies in the 8%–17% range alongside MED12 alterations and CDKN2A deletions PMID:37315267.
  • CDK4 amplifications and CDKN2A deletions were mutually exclusive, enriched in acral and high-risk lesions, and correlated with poor overall survival (P=.02) PMID:37315267.
  • Focal CDK4 amplifications (along with MYCN and PDGFRA) were used to define “molecular grade-intermediate” in 1p19q intact IDH-mutant astrocytomas in a 128-patient MSKCC active-surveillance cohort PMID:37910594.
  • CDK4 amplification detected in 17% of FP-RMS in a multi-platform ctDNA study; often co-amplified with GLI1 (2 tumors) or MDM2 (1 tumor) at the 12q13-15 locus; correlated with worse OS; identified as a high-risk secondary event alongside MYCN and CDKN2A alterations PMID:37730754.
  • CDK4 alterations designated as markers warranting shorter ctDNA surveillance intervals during follow-up in FP-RMS PMID:37730754.
  • CDK4 cited in the introduction as a prevalent CDK aberration in liposarcoma (LIPO) literature; CDK4/6 inhibitor palbociclib tested across sarcoma patient-derived tumor organoids (PDTOs) in a functional precision medicine study of 194 sarcoma specimens PMID:39305899.
  • Altered (e.g. amplification) in 18% of GBM samples as part of the RB pathway PMID:18772890.
  • Focal 12q amplification in ~90% of dedifferentiated liposarcoma (DDLS); CDK4 was the most overexpressed amplified hit relative to normal fat in a 385-gene shRNA screen; sustained CDK4 knockdown (>10 days) inhibited proliferation in LPS141 and DDLS8817 cell lines; pharmacologic inhibition with palbociclib (PD0332991) induced G1 arrest — first functional validation of CDK4 as a therapeutic dependency in DDLS (sarc_mskcc, n=207) PMID:20601955.
  • Identified as mutated in LUAD (TSP, n=188); cell cycle pathway member; co-altered with CDK6, CCND1, CCNE1, and CDKN2A/B in cell cycle pathway disruption. PMID:18948947
  • CDK4 amplification in 5% of GBC (oncogenic CNA) PMID:36228155
  • Upregulated in basal-like IntClust 10 as part of a chromosome 5q deletion-associated trans-acting mitotic network in the METABRIC breast cancer cohort (2,000 tumors) PMID:22522925
  • CDK4 amplification is identified in the Yale melanoma WES cohort of 147 tumors, frequently co-occurring with CCND1 amplification as a mechanism of RB pathway bypass PMID:22842228
  • CDK4 amplification is recurrent in the Broad melanoma WES cohort of 121 tumors, providing an alternative mechanism of RB pathway inactivation alongside CDKN2A deletion PMID:22817889
  • Amplified in breast cancer (TCGA, 510 tumors); CDK4 amplification identified as a recurrent copy-number alteration in luminal B and HER2-enriched subtypes, collaborating with CCND1 to drive G1/S progression PMID:23000897
  • Recurrent focal amplification in GBM; chr12 double-minute co-amplification with MDM2 was a striking structural finding; CDK4/CDK6 amplifications contribute to Rb-pathway dysregulation (overall 78.9%) PMID:24120142
  • Downstream effector of the RB pathway deregulated by TMZ-associated CDKN2A P114L mutation; CDK4 inhibition was abrogated by CDKN2A mutation, contributing to malignant progression in TMZ-treated recurrent low-grade glioma PMID:24336570
  • Within 12q13-q14 amplicon in 9.7% of rhabdomyosarcoma (RMS) cases, skewed toward PAX-fusion-positive tumors; 12q amplification containing CDK4 associated with worse overall survival in RMS independent of fusion status PMID:24436047
  • Dalpiciclib (CDK4/6 inhibitor) induces G1 arrest and upregulates MHC class I/IFN signaling; combined with camrelizumab achieved ORR 32.4% in PD-1-refractory R/M NPC PMID:24952746
  • High-level copy-number gain in 2 of 29 cutaneous squamous cell carcinoma samples by GISTIC analysis PMID:25589618
  • Amplification in 9% of PDA (RB-pathway alteration); co-occurs with CDKN2A/B deletion (36% each) and CCND1 amplification (6%); nominates CDK4/6 inhibitors PMID:25855536
  • Cell-cycle pathway aberration in mCRPC; potentially actionable via CDK4 inhibition; part of RB1/CDKN2A/B/CDK4/CCND1/CDKN1B cluster PMID:26000489
  • Focal amplifications enriched in Triple-WT melanoma subtype; co-amplified with CCND1 PMID:26091043
  • Focal amplification (IHC-confirmed) in desmoplastic melanoma; CDK4 is explicitly named as a small-molecule inhibitor target in this tumor type given the absence of BRAF V600E PMID:26343386
  • Mentioned in study PMID:26824661
  • CDK4 harbored a recurrent p.R24L mutation in lung adenocarcinoma identified in the TCGA Pan-Lung analysis PMID:27158780.
  • CDK4 co-overexpression with MDM2 in neuroblastoma (NBL); patient enrolled on the NEPENTHE trial (NCT02780128) targeting CDK4/6 in the PIPseq pediatric precision-oncology cohort PMID:28007021
  • CDK4 — recurrent copy gain on Chr 12, with significance retained specifically in metastatic ALM subsets; mutually exclusive patterns with CDKN2A deletion on Chr 9 PMID:28373299
  • Amplification in 2/19 (10.5%) anaplastic oligodendroglioma tumors sequenced by MSK-IMPACT 410; classified OncoKB Level 2B (FDA-recognized biomarker predictive of response in another indication) PMID:28472509
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Cancer types (linked)

  • Extremity rhabdomyosarcoma (ARMS) — CDK4 amplification is a recurrent, prognostically adverse event PMID:37315267.
  • FP-RMS (RMS/ARMS) — CDK4 amplification in 17% of FP-RMS; co-amplified with GLI1 or MDM2; adverse prognosis marker warranting ctDNA-based monitoring PMID:37730754.

Co-occurrence and mutual exclusivity

  • CDK4 amplification is mutually exclusive with CDKN2A deletion in extremity ARMS, consistent with convergent cell-cycle/RB-pathway dysregulation PMID:37315267.

Therapeutic relevance

  • The authors argue CDK4 amplifications should be considered for integration into RMS risk stratification, and raise CDK4/6-directed therapy as a rationale, though efficacy is untested in this cohort PMID:37315267.

Open questions

  • Whether CDK4/6 inhibition improves outcomes in CDK4-amplified or CDKN2A-deleted extremity RMS remains untested PMID:37315267.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:18948947

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22522925

This page was processed by crosslinker on 2026-05-14. - PMID:22842228

This page was processed by crosslinker on 2026-05-14. - PMID:22817889

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:24120142

This page was processed by crosslinker on 2026-05-14. - PMID:24336570

This page was processed by crosslinker on 2026-05-14. - PMID:24436047

This page was processed by crosslinker on 2026-05-14. - PMID:24952746

This page was processed by crosslinker on 2026-05-14. - PMID:25589618

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26343386

This page was processed by crosslinker on 2026-05-14. - PMID:26824661

This page was processed by wiki-cli on 2026-05-14. - PMID:27158780

This page was processed by wiki-cli on 2026-05-14. - PMID:28007021

This page was processed by wiki-cli on 2026-05-14.

This page was processed by entity-page-writer on 2026-05-15. - PMID:28373299

This page was processed by entity-page-writer on 2026-05-15. - PMID:28472509

This page was processed by entity-page-writer on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

This page was processed by wiki-cli on 2026-05-15.