Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model

ANA R. RAIMONDI, ALFREDO MOLINOLO, AND J. SILVIO GUTKIND

Bethesda, MD, USA

Conferencia; Molecular Targets for Cancer Prevention Conference; 2009

National Cancer Institute, National Institute of Health (NIH), USA

Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. A major limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis, and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifen-inducible Cre recombinase (CreERtam) under the control of the cytokeratin 14 (K14) promoter (K14-CreERtam) and mice in which the endogenous K-ras locus is targeted (LSL-K-rasG12D), thereby causing the expression of endogenous levels of oncogenic K-rasG12D following removal of a stop element. Surprisingly, whereas K14-CreERtam can also target the skin, K14-CreERtam/LSL-K-rasG12D mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knock out (p53flox/flox) mice, the compound animals developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mTOR signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. In this regard, we show that the activation of the mTOR signaling pathway is an early event in both oral benign and malignant lesions, and that targeting mTOR by the use of rapamycin halts tumor progression in this genetically defined oral cancer model, thereby prolonging animal survival.