Conventional and alternative approaches for targeting PIK3CA and PTEN alterations in head and neck, breast, and other cancers.

Genetic alterations in genes encoding components of the PI3K/AKT/mTOR signaling pathway are frequently observed in head and neck squamous cell carcinoma (HNSCC), breast cancer, and a variety of other human malignancies. In particular, PIK3CA, encoding the p110α catalytic subunit of PI3K enzyme, is altered in approximately 30 % of HNSCC tumors and 37 % of breast cancer tumors. In addition, loss of PTEN protein, a negative regulator of PI3K signaling, occurs in roughly one-third of HNSCC. Here, we review the impact of these alterations on the growth and metabolism of cancer cells and summarize progress that has been made in the development and clinical evaluation of inhibitors that directly target p110α and related proteins. We also describe emerging approaches that are identifying unique vulnerabilities and targeting opportunities in tumors characterized by PIK3CA or PTEN alterations.