by Sotillo, Rocío, Renner, Oliver, Dubus, Pierre, Ruiz-Cabello, Jesus, Martín-Caballero, Juan, Barbacid, Mariano, Carnero, Amancio and Malumbres, Marcos
Abstract:
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.
Reference:
Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity. (Sotillo, Rocío, Renner, Oliver, Dubus, Pierre, Ruiz-Cabello, Jesus, Martín-Caballero, Juan, Barbacid, Mariano, Carnero, Amancio and Malumbres, Marcos), In Cancer Research, American Association for Cancer Research, volume 65, 2005.
Bibtex Entry:
@article{Sotillo:2005hma,
author = {Sotillo, Roc{'i}o and Renner, Oliver and Dubus, Pierre and Ruiz-Cabello, Jesus and Mart{'i}n-Caballero, Juan and Barbacid, Mariano and Carnero, Amancio and Malumbres, Marcos},
title = {{Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity.}},
journal = {Cancer Research},
year = {2005},
volume = {65},
number = {9},
pages = {3846--3852},
month = may,
publisher = {American Association for Cancer Research},
affiliation = {Molecular Oncology, Centro Nacional de Investigaciones Oncol{'o}gicas (CNIO), Madrid, Spain.},
doi = {10.1158/0008-5472.CAN-04-4195},
pmid = {15867383},
language = {English},
rating = {0},
date-added = {2018-03-16T12:59:30GMT},
date-modified = {2020-07-09T13:27:51GMT},
abstract = {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.},
url = {http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-04-4195},
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uri = {url{papers3://publication/doi/10.1158/0008-5472.CAN-04-4195}}
}