Molecule Information

General Information of the Molecule (ID: Mol00042)

• Name: Cyclin-dependent kinase 4 (CDK4) ,Homo sapiens
• Synonyms: Cell division protein kinase 4; PSK-J3
• Molecule Type: Protein
• Gene Name: CDK4
• Gene ID: 1019
• Location: chr12:57747727-57756013[-]
• Sequence:
  MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
  RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL
  MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY
  RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR
  DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG
  NPE
• 3D-structure: PDB ID: 5FWK; Classification: Signaling protein; Method: Electron microscopy; Resolution: 3.90 Å
• Function: Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.
• Uniprot ID: CDK4_HUMAN
• Ensembl ID: ENSG00000135446
• HGNC ID: HGNC:1773

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Palbociclib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-37; Fold-change: 5.96E-02; Z-score: 1.38E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Various mechanisms, such as gene amplification, mutations and epigenetic alterations, serve to activate the cyclin D-CDK4/6-RB pathway. Overexpression of CDK4, which has been described in several cancers, may limit the efficacy of CDK4/6 inhibitors.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Palbociclib
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [5]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Palbociclib
• Molecule Alteration: Missense mutation; p.R24C (c.70C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: SRB assay

Copanlisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [2]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Sensitive Drug: Copanlisib
• Molecule Alteration: Expression; Express CDK4
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Molecule Alteration: Protein component assay; Immunoblotting assay; Immunofluorescence staining assay
• Experiment for Drug Resistance: Cell viability assay; Synergistic effects assay; Cell growth rates assay
• Mechanism Description: Considering the fact that for many tumour cells, inhibition of CDK4/6 can induce cellular quiescence or senescence, we evaluated whether CDK4 expression was affected by copanlisib alone or in combination with palbociclib. Copanlisib was selected as it was more effective than other PI3K inhibitors on its own. While the cells did not react to palbociclib by reducing the expression of CDK4, copanlisib lead to dose-dependent downregulation in CDK4 expression, especially when combined with palbociclib (Additional file 1: Fig. S8). Moreover, the cells did not express p-Akt following treatment with copanlisib (Additional file 1: Fig. S9).

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [3]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: As a potential tumor suppressor, miR206 directly targets CDk4 to suppress the cell growth and enhance the chemotherapy sensitivity to 5-Fu in ovarian cancer cells in vitro.

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: LY2835219
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Various mechanisms, such as gene amplification, mutations and epigenetic alterations, serve to activate the cyclin D-CDK4/6-RB pathway. Overexpression of CDK4, which has been described in several cancers, may limit the efficacy of CDK4/6 inhibitors.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Ribociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Various mechanisms, such as gene amplification, mutations and epigenetic alterations, serve to activate the cyclin D-CDK4/6-RB pathway. Overexpression of CDK4, which has been described in several cancers, may limit the efficacy of CDK4/6 inhibitors.

Trilaciclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Triple negative breast cancer [ICD-11: 2C60.9] [6]

• Resistant Disease: Triple negative breast cancer [ICD-11: 2C60.9]
• Resistant Drug: Trilaciclib
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Mechanism Description: Trilaciclib, a small molecule short-acting inhibitor of CDK4/6, has also been approved recently for people with small cell lung cancer, and is also expected to be clinically effective against breast cancer. r\Reducing Rb phosphorylation promotes AKT pathway activity, which may result in CDK4/6 inhibitor resistance. Trilaciclib, an intravenous and competitive CDK4/6 inhibitor, has been shown to reduce the myelotoxicity of chemotherapeutic agents by inducing transient cell cycle arrest. This drug can differentially inhibit both cytotoxic and regulatory T cells.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.30E-72; Fold-change: 6.47E-01; Z-score: 2.39E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.75E-25; Fold-change: 6.16E-01; Z-score: 1.26E+00

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.54E-06; Fold-change: 7.07E-01; Z-score: 1.24E+00

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-37; Fold-change: 4.17E-01; Z-score: 1.08E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.19E-02; Fold-change: 3.18E-02; Z-score: 5.19E-02

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.00E-01; Fold-change: 3.54E-01; Z-score: 8.79E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.57E-02; Fold-change: 7.12E-01; Z-score: 6.93E-01

References

• Ref 1: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020
• Ref 2: Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia. Cancer Cell Int. 2023 Aug 11;23(1):161.
• Ref 3: [Role of miR-206/CDK4 in modulating the growth and chemotlerapy sensitivity of ovarian cancer cells]. Nan Fang Yi Ke Da Xue Xue Bao. 2017 Mar 20;37(3):393-397. doi: 10.3969/j.issn.1673-4254.2017.03.20.
• Ref 4: A phase II study of palbociclib (P) for previously treated cell cycle gene alteration positive patients (pts) with stage IV squamous cell lung cancer (SCC): Lung-MAP sub-study SWOG S1400C.
• Ref 5: Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell linesPigment Cell Melanoma Res. 2014 Jul;27(4):590-600. doi: 10.1111/pcmr.12228. Epub 2014 Mar 6.
• Ref 6: Potential Prospect of CDK4/6 Inhibitors in Triple-Negative Breast Cancer .Cancer Manag Res. 2021 Jul 1;13:5223-5237. doi: 10.2147/CMAR.S310649. eCollection 2021. 10.2147/CMAR.S310649