Genomic predictors of drug response to the alpha-specific phosphoinositol 3-kinase (PI3Ka-alpha) inhibitor BYL719 in head and neck cancers
Master of Science
Anatomy and Cell Biology
Dr. Anthony Nichols
PIK3CA is the only frequently mutated, druggable oncogene in head and neck squamous cell cancer (HNSCC), with PIK3CA point mutations and gene amplification rates of 17.5% and 40% respectively, with higher rates in HPV-positive disease. The objective of this research was to determine the effects of BYL719, an α-specific PI3K inhibitor in HNSCC cell lines.
All cell lines with PIK3CA hotspot point mutations or gene amplifications will be sensitive to BYL719.
Twenty-eight HNSCC cell lines were subjected to increasing concentrations of BYL719 and cell viability was measured over time. Cell lines were screened for activating PIK3CA hotspot mutations and amplifications by real time PCR. Activity of PI3K pathway members was determined by immuniblot.
All PIK3CA cell lines with hotspot point mutations were sensitive to BYL719 treatment, whereas all PIK3CA amplified cell lines were resistant. Moreover, resistant cell lines showed persistent protein activation of mTORC1, as determined by continued phosphorylation of ribosomal protein S6 following BYL719 treatment. Combination drug therapy with rapamycin, an mTORC1 inhibitor, reduced cell viability in BYL719-resistant cell lines. Nearly all PIK3CA amplified cell lines showed co-amplification of PIK3CA with SOX2 genes. Theses findings will help determine which population of patients will benefit most from BYL719 treatment.
Rizzo, Giananthony T., "Genomic predictors of drug response to the alpha-specific phosphoinositol 3-kinase (PI3Ka-alpha) inhibitor BYL719 in head and neck cancers" (2014). Electronic Thesis and Dissertation Repository. 2170.
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