@article{3b2e5165623447a2956c520b482f849c,
title = "Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma",
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.",
author = "Nan Jin and Bhumsuk Keam and Janice Cho and Lee, {Michelle J.} and Kim, {Hye Ryun} and Hayarpi Torosyan and Natalia Jura and Ng, {Patrick K.S.} and Mills, {Gordon B.} and Hua Li and Yan Zeng and Zohar Barbash and Gabi Tarcic and Hyunseok Kang and Bauman, {Julie E.} and Kim, {Mi Ok} and VanLandingham, {Nathan K.} and Swaney, {Danielle L.} and Krogan, {Nevan J.} and Johnson, {Daniel E.} and Grandis, {Jennifer R.}",
note = "Funding Information: Conflict of interest: JRG and DEJ are coinventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics, Inc. STAT3 Therapeutics, Inc. holds an interest in the cyclic STAT3 decoy oligonucleotide. ZB and GT are full-time employees of NovellusDx. The Krogan Laboratory received research support from Vir Biotechnology and F. Hoffmann-La Roche. NJK has consulting agreements with Maze Therapeutics and Interline Therapeutics. GBM is a member of the consultant/scientific advisory boards of Amphista Therapeutics, Astra-Zeneca, Chrysalis Biotechnology, GSK, ImmunoMet, Ionis, Eli Lilly, PDX Pharmaceuticals, SignalChem, Symphogen, Tarveda Therapeutics, Turbine, and Zentalis Pharmaceuticals. GBM has financial interests in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. The Mills Laboratory received foundation support from Adelson Medical Research Foundation; research support from NanoString Center of Excellence and Ionis (provision of tool compounds); and clinical trial support from AstraZeneca, Genentech, GSK, and Eli Lilly. The Mills Laboratory has licensed a homologous recombination deficiency assay to Myriad Genetics and digital spatial profiler to NanoString. JEB received clinical research grants from AstraZeneca, Aveo, Bristol Myers Squibb, Celldex, CUE Biopharma, Eli Lilly, and Novartis. Copyright: {\textcopyright} 2021, American Society for Clinical Investigation. Submitted: April 7, 2021; Accepted: September 21, 2021; Published: November 15, 2021. Reference information: J Clin Invest. 2021;131(22):e150335. https://doi.org/10.1172/JCI150335. Funding Information: This work was supported by NIH grants R01 DE023685 (to JRG and DEJ), R35 CA231998 (to JRG), U54CA209891 (to NJK), and U01 CA217842 (to GBM) and the Howard Hughes Medical Institute Medical Research Fellows Program (to JC), and a translational grant from the V Foundation for Cancer Research (to JEB and JRG). The TRIUMPH trial was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA16C0015). Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = nov,
day = "15",
doi = "10.1172/JCI150335",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "22",
}