Figure 1.

Main targets and related signaling pathways involved in the targeted therapy for R/M HNSCC. Activation of EGFR by extracellular ligands initiates activation of Src, STAT3, and PI3K. Activated Src promotes cell proliferation mainly via RAS/RAF/MAPK pathway. In the PI3K/Akt pathway, phosphorylation of PIP2 is mediated by PI3K while dephosphorylation of PIP3 is controlled by PTEN. Akt could be activated independently by mTORC2 activation. Activation of Akt and mTORC1 inhibit TSC1/2/Rheb and 4E-BP1/eIF-4E downstream signaling, respectively while IKK/NF-kB and S6/S6k pathways are initiated, promoting tumor cell survival. Once activated, other targets, including VEGFR and c-MET, expressed on tumor cells share similar downstream signaling with EGFR. CD137L and OX40L activate CD137 and OX40, respectively. And proliferation of activated T cells is achieved via TRAF/IKK/NF-κB downstream signaling. CTLA-4 and its ligands are also demonstrated. Some pathways were simplified for clearer demonstration.