Journal Article

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma

Torosyan, Hayarpi, Li, Hua, Ng, Patrick K.S., Kang, Hyunseok, Jin, Nan, VanLandingham, Nathan K., Krogan, Nevan J., Barbash, Zohar, Grandis, Jennifer R., Johnson, Daniel E., Tarcic, Gabi, Keam, Bhumsuk, Lee, Michelle J., Jura, Natalia, Kim, Hye Ryun, Kim, Mi-Ok, Cho, Janice, Zeng, Yan, Bauman, Julie E., Mills, Gordon B., Swaney, Danielle L.

2021

Overview

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antitumor activity / Biomarkers / Biomedical research / Breast cancer / Cancer / Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Class I Phosphatidylinositol 3-Kinases - chemistry / Class I Phosphatidylinositol 3-Kinases - genetics / Class I Phosphatidylinositol 3-Kinases - physiology / Drug sensitization / Drug therapy / FDA approval / Gene mutations / Genetic aspects / Head & neck cancer / Head and neck cancer / Head and neck carcinoma / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - genetics / Health aspects / Human papillomavirus / Humans / Kinases / Male / Mice / Middle Aged / Mutation / Oncology, Experimental / Patients / Phenotypes / Protein Domains / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - drug therapy / Squamous Cell Carcinoma of Head and Neck - genetics / Thiazoles - therapeutic use / Transferases / Tumors / Xenografts