Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.

Wirtz ED, Hoshino D, Maldonado AT, Tyson DR, Weaver AM
JAMA Otolaryngol Head Neck Surg. 2015 141 (6): 543-9

PMID: 25855885 · PMCID: PMC4474763 · DOI:10.1001/jamaoto.2015.0471

IMPORTANCE - The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation.

OBJECTIVES - (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies.

DESIGN, SETTING, AND PARTICIPANTS - This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy.

EXPOSURES - PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235.

MAIN OUTCOMES AND MEASURES - Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R.

RESULTS - Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance.

CONCLUSIONS AND RELEVANCE - (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of PI3K-overactive HNSCC tumors.

MeSH Terms (22)

Benzoquinones Carcinoma, Squamous Cell Cell Line, Tumor Cell Survival Class I Phosphatidylinositol 3-Kinases Head and Neck Neoplasms Humans Imidazoles Indazoles Inhibitory Concentration 50 Lactams, Macrocyclic Molecular Targeted Therapy Mutation Phosphatidylinositol 3-Kinases Protein-Serine-Threonine Kinases Pyridones Pyrimidinones Quinolines Squamous Cell Carcinoma of Head and Neck Sulfonamides TOR Serine-Threonine Kinases Tumor Cells, Cultured

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