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Abstract A39: PI3K inhibition in preclinical models of HNSCC

Head and neck squamous cell carcinoma (HNSCC) is characterized by alteration of the PI3K pathway; especially mutation and/or amplification of the oncogene PIK3CA, and these alterations are enriched in HNSCC associated with human papilloma virus infection (HPV(+)HNSCC). We sought to test the hypothes...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2015-07, Vol.14 (7_Supplement), p.A39-A39
Main Authors: Hedberg, Matthew Louis, Li, Hua, Zeng, Yan, Grandis, Jennifer Rubin
Format: Article
Language:English
Online Access:Get full text
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Summary:Head and neck squamous cell carcinoma (HNSCC) is characterized by alteration of the PI3K pathway; especially mutation and/or amplification of the oncogene PIK3CA, and these alterations are enriched in HNSCC associated with human papilloma virus infection (HPV(+)HNSCC). We sought to test the hypothesis that HNSCC cells/tumors with mutant or amplified PIK3CA are more sensitive to anti-tumor effects of PI3K pathway inhibitors, including BKM-120 and BYL-719, and to assess the effect of HPV status on the efficacy of these agents. Proliferation assays and immunobloting were employed to examine the effects on growth and signaling of BKM-120 and BYL-719 administration to HNSCC cell lines with endogenous PIK3CA mutation, gene amplification, or WT, unamplified PIK3CA. The cytotoxic effects of BKM-120 and BYL-719 were comparable in a panel of 8 HNSCC cell lines, with IC50s in the micromolar range. BYL-719 demonstrated greater cytotoxic activity in cell lines with endogenous PIK3CA alterations compared with cells harboring endogenous WT, unamplified PIK3CA. Treatment with BKM-120 decreased the levels of phosphorylated AKT in a dose-dependent fashion to a greater degree in PIK3CA altered cells than in PIK3CA WT cells. In contrast, BYL-719 treatment inhibited phosphorylation of AKT in both PIK3CA altered and PIK3CA WT HNSCC cells, with comparable efficacy. Phosphorylation of S6 and MTOR however, was inhibited by BYL-719 to a greater degree in PIK3CA altered cell lines vs. PIK3CA WT cell lines. More than half of all HPV(+)HNSCC harbor some form of PI3K alteration; generally PIK3CA mutation or amplification. However, there is a paucity of HPV(+)HNSCC cell lines, and no cell lines to date derived from HPV(+)HNSCC tumors contain PIK3CA mutations. Although we included two HPV(+)HNSCC cell lines in our studies, neither are known to harbor endogenous PIK3CA mutations, and they did not appear to be more sensitive to PI3K pathway targeting with BKM-120 or BYL-719. Our in vivo treatment experiments, utilizing patient derived xenografts (PDX) of varying HPV and PIK3CA status, demonstrate that the growth of HPV(+)HNSCC tumors can be inhibited by BYL-719 treatment to a greater degree than the growth of HPV(-)HNSCC tumors. These cumulative findings suggest that PI3K inhibition may represent an effective therapeutic strategy in the subset of HNSCC patients whose tumors harbor PI3K alteration. As the PI3K pathway is the most commonly altered mitogenic pathway in HNSCC; the completion o
ISSN:1535-7163
1538-8514
DOI:10.1158/1538-8514.PI3K14-A39