Figure 1: The PI3K-PTEN-mTOR pathway. Activation of PI3K pathway via exogenous stimuli, endogenous signals and/or mutations promotes cancer formation, progression and resistance to therapy. The major signal modulators are PI3K in green and PTEN in red. The PI3Ks are shown as a simplified heterodimeric complex that combines the PI3K regulatory and catalytic subunits discussed in this review. As seen in the schematic representation, activated upstream cellular receptors (i.e. RTKs, GFRs, GPCRs) lead to activation of PI3Ks, which phosphorylate its membrane phospholipid substrate (i.e PIP2 into PIP3). PTEN is a phosphatase that opposes PI3K action; therefore, mutation or ablation of PTEN leads to PI3K/mTOR pathway over activation. Next, AKT is translocated to the cell membrane and is phosphorylated by PDK1 and PDK2. Once AKT is activated, it inhibits TSC1/TSC2 complex, which leads to RHEB inhibition. mTOR complexes (mTORC1 and mTORC2) collect the signals. mTORC1 activates downstream molecules. As a result, mTORC1 controls major processes, including cell cycle progression, growth, protein synthesis, lipid synthesis, and autophagy. mTORC2 functions are less understood, yet it is known to regulated, cell shape, cytoskeleton organization, cell survival, and cell metabolism. Therefore, PI3K/PTEN/mTOR pathway can control essential cancer cell processes, such as growth, invasion, metastases, and response to therapy. Black circles identify proteins that were found mutated in HNSCC. RTK: receptors of tyrosine kinase; GFR: growth factors receptors; PI3K: phosphatidylinositol 3-kinase; PIP2: Phosphatidylinositol 4,5-bisphosphate or PtdIns [4,5] P2; PIP3: Phosphatidylinositol [3-5]-trisphosphate or PtdIns [3-5] P3; PTEN: Phosphatase and tensin homolog; MAPK: Mitogen-activated protein kinases; FOXO: forkhead box O; GSK3: glycogen-synthase-kinase-3; PKC: protein kinase C; Rac1: ras-related C3 botulinum toxin substrate 1; SGK1: serum/glucocorticoid regulated kinase 1; S6K: ribosomal protein S6 kinase; TSC1/2: tuberous sclerosis 1/2; 4E-BP1: eukaryotic initiation factor 4E-binding protein 1; eEF-4E: Eukaryotic translation initiation factor 4E; Rheb: Ras homolog enriched in brain; mTORC1/2: rapamycin-sensitive mTOR complex 1 and 2.