Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity

Cancer Res. 2005 May 1;65(9):3846-52. doi: 10.1158/0008-5472.CAN-04-4195.


Deregulation of the G1-S transition of the cell cycle is a common feature of human cancer. Tumor-associated alterations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27Kip1), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development. Using gene-targeted mouse models, we report in this article that Cdk4 resistance to INK4 inhibitors, due to the Cdk4 R24C mutation, strongly cooperates with p27(Kip1) deficiency in tumor development. No such cooperation is observed between Cdk4 R24C and p18(INK4c) absence, suggesting that the only function of p18INK4c is inhibiting Cdk4 in this model. Cdk4(R/R) knock in mice, which express the Cdk4 R24C mutant protein, develop pituitary tumors with complete penetrance and short latency in a p27Kip1-/- or p27Kip1+/- background. We have investigated whether this tumor model could be useful to assess the therapeutic activity of cell cycle inhibitors. We show here that exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumor-free survival in a significant percentage of treated mice. These data suggest that genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Cycle Proteins / genetics
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / genetics*
  • Disease Models, Animal
  • Flavonoids / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Piperidines / pharmacology*
  • Pituitary Neoplasms / drug therapy*
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / pathology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics


  • Antineoplastic Agents
  • Cdkn1b protein, mouse
  • Cdkn2c protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p18
  • Flavonoids
  • Piperidines
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • alvocidib
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases