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

Document Type

Article

Publication Date

11-15-2021

Publication Title

The Journal of clinical investigation

Keywords

JGM, Animals, Class I Phosphatidylinositol 3-Kinases, Head and Neck Neoplasms, Humans, Male, Mice, Middle Aged, Mutation, Protein Domains, Squamous Cell Carcinoma of Head and Neck, Thiazoles

JAX Source

J Clin Invest 2021 Nov 15; 131(22):e150335

Volume

131

Issue

22

ISSN

1558-8238

PMID

34779417

DOI

https://doi.org/10.1172/jci150335

Abstract

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.

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