Therapeutic Implications of the Genetic Landscape of Head and Neck Cancer

Abstract

Large-scale sequencing studies of head and neck squamous cell carcinoma (HNSCC) have elucidated the genetic changes that characterize HNSCC. These findings have supported the development of therapeutic strategies that target key components of aberrant signaling pathways and immune dysregulation. Cumulative evidence suggests that these agents in combination with radiotherapy may have synergistic effects. This review highlights the predictive biomarkers that have been identified from HNSCC genomic studies and implications on the development of molecular-targeting agents that may effectively treat patients with HNSCC, especially when used in combination with radiation.

Figure 1.. Components of the phosphoinositide 3-kinase (PI3K) signaling pathway and its associated therapeutic targets.

Binding of growth factors and cytokines to a receptor tyrosine kinase (RTK) located on the cell membrane activates class I PI3K, which is a heterodimer of p85 and a p110 isoform (p110α is illustrated here). The catalytic subunit of PI3K (p110α) phosphorylates phosphatidylinositol 4,5-biphosphate (PIP₂), generating phosphatidylinositol (3,4,5)-triphosphate (PIP₃). PIP3 activates protein kinase B (Akt), which subsequently triggers mTOR (mechanistic target of rapamycin) activity. Therapeutic targets that inhibit various components of this signaling pathway include the following: p110α inhibitor (alpelisib/BYL719), pan PI3K inhibitors (buparlisib/BKM120, copanlisib/BAY-80–6946, PX-866, and SF1126), dual PI3K/mTOR inhibitor (BEZ-253), Akt inhibitor (MK-2206), and mTOR inhibitors (sirolimus/rapamycin, everolimus, and temsirolimus).