PI3K/AKT/mTOR signaling as a molecular target in head and neck cancer.

The aim of this review is to summarize current available information about the role of PI3K/AKT/mTOR signaling in head and neck cancer as a potential target for new therapy options. 90% of all head and neck cancers are squamous cell carcinomas (HNSCC). The most common genetic alteration is inactivation of p16 gene which is cyclin dependent kinase inhibitor 2A. HNSCC are divided into human papilloma virus (HPV) related and HPV-negative carcinomas. HPV related carcinomas of patients who do not have a history of tobacco and alcohol consumption have better prognosis. Until now, HNSCC are treated with surgical removal of cancer tissue in primary region and lymph nodes combined with radiotherapy, cytostatic drugs and in some cases, epidermal growth factor receptor (EGFR) targeted antibody cetuximab and programmed death receptor-1 (PD-1) antibodies. PI3K/AKT/mTOR signaling is active in over 90% of HNSCC, as a result of EGFR activation (47%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations (8.6%), PIK3CA amplifications (14.2%), phosphatidylinositol 3-kinase (PI3K) overexpression (27.2%) and phosphatase and tensin homolog (PTEN) mutation (10-15%). Activated PI3K/AKT/mTOR signaling is related to radiotherapy and cytostatic drug resistance, likely through enhanced DNA-repair mechanisms. Inhibitors against PI3K, AKT and mammalian target of rapamycin (mTOR) have remarkable effects on tumor cell proliferation and radiotherapy sensitization in cell cultures and mouse models. Nevertheless, feedback mechanisms, like activation of AKT after mTOR treatment, reduce efficiency. Therefore, combined therapy should be investigated. PI3K, AKT and mTOR inhibitors achieved tumor response in 5.3%, 2.8% and 31% when given as monotherapy, respectively. When combined to cytostatic drugs, 29.2% and 43.5% of all patients showed a response to PI3K and mTOR inhibitors, respectively. A study investigating everolimus (Rad001) with cisplatin and radiotherapy has reported promising 2-year progression free survival and overall survival rates of 85% and 92%. Further clinical trials should follow.