The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most frequently dysregulated signaling cascades in HNSCC, with evidence of activation in over 90% of tumors across both HPV-positive and HPV-negative subsets [31,47,48]. This evidence concerns the gene PIK3CA and head and neck squamous cell carcinoma.