Data from Cooperation between Cdk4 and p27<sup>kip1</sup> in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity

Abstract

<div>Abstract<p>Deregulation of the G<sub>1</sub>-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 p27<sup>Kip1</sup>), 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<sup>Kip1</sup> deficiency in tumor development. No such cooperation is observed between Cdk4 R24C and p18<sup>INK4c</sup> absence, suggesting that the only function of p18<sup>INK4c</sup> is inhibiting Cdk4 in this model. <i>Cdk4</i><sup>R/R</sup> knock in mice, which express the Cdk4 R24C mutant protein, develop pituitary tumors with complete penetrance and short latency in a <i>p27</i><sup>Kip1−/−</sup> or <i>p27</i><sup>Kip1+/−</sup> 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.</p></div>