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Cooperation between Cdk4 and p27^kip1 in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity

¹ Molecular Oncology, ² Experimental Therapeutics, and ³ Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas (CNIO); ⁴ Instituto de Estudios Biofuncionales, Madrid, Spain; and ⁵ University of Bordeaux 2, Bordeaux, France

Requests for reprints: Marcos Malumbres, Centro Nacional de Investigaciones Oncológicas, Molecular Oncology, Melchor Fernández Almagro 3, E-28029 Madrid, Spain. Phone: 34-91-2246900; Fax: 34-91-7328033; E-mail: mmm{at}cnio.es.

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 p27^Kip1), 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 p18^INK4c 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 p27^Kip1–/– or p27^Kip1+/– 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.

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