Molecule Information

General Information of the Molecule (ID: Mol00289)

• Name: Cyclin-dependent kinase inhibitor 2A (CDKN2A) ,Homo sapiens
• Synonyms: Cyclin-dependent kinase 4 inhibitor A; CDK4I; Multiple tumor suppressor 1; MTS-1; p16-INK4a; p16-INK4; p16INK4A; CDKN2; MTS1
• Molecule Type: Protein
• Gene Name: CDKN2A
• Gene ID: 1029
• Location: chr9:21967752-21995301[-]
• Sequence:
  MEPAAGSSMEPSADWLATAAARGRVEEVRALLEAGALPNAPNSYGRRPIQVMMMGSARVA
  ELLLLHGAEPNCADPATLTRPVHDAAREGFLDTLVVLHRAGARLDVRDAWGRLPVDLAEE
  LGHRDVARYLRAAAGGTRGSNHARIDAAEGPSDIPD
• 3D-structure: PDB ID: 7OZT; Classification: Cell cycle; Method: X-ray diffraction; Resolution: 1.74 Å
• Function: Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.
• Uniprot ID: CDN2A_HUMAN
• Ensembl ID: ENSG00000147889
• HGNC ID: HGNC:1787

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

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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: 7.16E-27; Fold-change: 1.60E-01; Z-score: 1.12E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Overexpression of p16 occurs during oncogenic stress, with or without the loss of RB. Loss of RB with concurrent p16 overexpression resulted in failure to respond to CDK4/6 inhibitors because of the absence of RB function. Alternatively, p16 overexpression in the presence of functional RB, also confers resistance to CDK4/6 inhibitors as a result of diminished CDK4, indicating depletion of a target of CDK4/6 inhibitors. Although the loss of RB and p16 overexpression seems to occur consequently together, further studies revealing the mechanistic association of RB loss and p16 overexpression might be beneficial in designing the strategies to overcome acquired resistance to CDK4/6 inhibitors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [4]

• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Sensitive Drug: Palbociclib
• Molecule Alteration: Nonsense; p.R80* (c.238C>T)
• Experimental Note: Identified from the Human Clinical Data

Decitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Osteosarcoma [ICD-11: 2B51.0] [2]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Decitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: HOTAIR-miR126-DNMT1-CDkN2A axis; Regulation; N.A.
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vitro Model: NHOst cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: HFob 1.19; Bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: RT-qPCR; ChIP assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR represses the expression of CDkN2A through inhibiting the promoter activity of CDkN2A by RNA hypermethylation. HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDkN2A axis.

Inotuzumab ozogamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Mature B-cell neoplasms [.] [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Resistant Drug: Inotuzumab ozogamicin
• Molecule Alteration: Missense mutation; Activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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: Overexpression of p16 occurs during oncogenic stress, with or without the loss of RB. Loss of RB with concurrent p16 overexpression resulted in failure to respond to CDK4/6 inhibitors because of the absence of RB function. Alternatively, p16 overexpression in the presence of functional RB, also confers resistance to CDK4/6 inhibitors as a result of diminished CDK4, indicating depletion of a target of CDK4/6 inhibitors. Although the loss of RB and p16 overexpression seems to occur consequently together, further studies revealing the mechanistic association of RB loss and p16 overexpression might be beneficial in designing the strategies to overcome acquired resistance to CDK4/6 inhibitors.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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: Overexpression of p16 occurs during oncogenic stress, with or without the loss of RB. Loss of RB with concurrent p16 overexpression resulted in failure to respond to CDK4/6 inhibitors because of the absence of RB function. Alternatively, p16 overexpression in the presence of functional RB, also confers resistance to CDK4/6 inhibitors as a result of diminished CDK4, indicating depletion of a target of CDK4/6 inhibitors. Although the loss of RB and p16 overexpression seems to occur consequently together, further studies revealing the mechanistic association of RB loss and p16 overexpression might be beneficial in designing the strategies to overcome acquired resistance to CDK4/6 inhibitors.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.35E-02; Fold-change: 5.44E-01; Z-score: 1.65E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.43E-05; Fold-change: 5.05E-01; Z-score: 7.57E-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: A novel interplay between HOTAIR and DNA methylation in osteosarcoma cells indicates a new therapeutic strategy. J Cancer Res Clin Oncol. 2017 Nov;143(11):2189-2200. doi: 10.1007/s00432-017-2478-3. Epub 2017 Jul 20.
• Ref 3: Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL. Blood. 2024 Jul 4;144(1):61-73.
• Ref 4: CDK4/6 inhibitor suppresses gastric cancer with CDKN2A mutationInt J Clin Exp Med. 2015 Jul 15;8(7):11692-700. eCollection 2015.