Head and Neck Cancer and the PI3K/Akt/mTOR Signaling Network: Novel Molecular Targeted Therapies

Abstract

Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common cancer among men worldwide. Despite significant advances in conventional therapies for other prevalent cancer types, the survival rate of HNSCC patients has barely improved over the past 3 decades, emphasizing the urgent need for the development of more effective treatment strategies. A better understanding of the mechanisms of tumorigenesis has led to novel molecular targeted options for cancer treatment. In this regard, we have observed that the persistent activation of the v-akt murine thymoma viral oncogene homolog 1Akt pathway is a frequent event in HNSCC. Akt promotes cell proliferation by coordinating mitogenic signaling with energy and nutrient-sensing pathways that control protein synthesis through the mammalian target of rapamycin (mTOR). This kinase, in turn, phosphorylates and activates key regulatory circuitries involved in mRNA translation, cell metabolism, and cell cycle control. Indeed, the activation of mTOR was found to be a widespread event in HNSCC, as judged by the detection of phospho-S6 (pS6), one of the most downstream targets of mTOR, in more than 80% of human HNSCCs. The promising development of mTOR inhibitors, including rapamycin (sirolimus) and its derivatives known as rapalogs, such as CCI-779 (temsilorimus), RAD001 (everolimus), and AP23573 (deferolimus), as antitumor agents prompted us to investigate the effects of rapamycin in HNSCC. Indeed, rapamycin treatment rapidly reduced the enhanced level of pS6 in vitro and in xenograft models. Furthermore, rapamycin displays a potent antitumor effect in vivo, as it induces apoptosis in HNSCC xenografts, and promotes the regression of chemically induced SCC lesions in skin and oral cancer models and in newly developed oral-specific, genetically defined mouse cancer models. In this chapter, we will describe a series of research efforts aimed at addressing dysregulated molecular mechanisms in HNSCC, focusing on the PI3K-Akt-mTOR signaling axis. We will also discuss recent and ongoing studies on the molecular targets of mTOR in HNSCC, and emerging experimental information supporting the ­effectiveness of mTOR inhibitors for the prevention and treatment of HNSCC.