Abstract
Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and standard treatment with surgery or chemoradiation has significant morbidity, with 5 year survival of <50%. Personalized targeted therapies with small molecule inhibitors have gained interest following identification of genetic drivers from The Cancer Genome Atlas (TCGA). TCGA data shows >60% of head and neck tumors harbor genomic alterations in the RTK-PI3K-mTOR and MAPK pathways important in cell growth and survival. In this study, we determined the effects of the novel PI3K-mTOR inhibitor PF-5212384 (PF-384) on molecular targets and HNSCC growth in preclinical models. PF-384 IC50s of 0.75nM-133nM were found in 12 HNSCC lines by XTT cell density assays and treatment resulted in increased sub-G0 cell death and G0/G1 phase blockade by DNA flow cytometry. PF-384 strongly inhibited direct targets of PI3K-mTOR, aberrant NF-kB transactivation and induced cytokines, but only partially inhibited MEK pathway targets. Transient siRNA knockdown of PIK3CA inhibited NF-kB activity, supporting PI3K-mTOR as an important driver and target for inhibition of NF-kB prosurvival signaling in HNSCC. PF-384 partially inhibited UMSCC1 tumor xenografts in vivo. PF-384 with MEK inhibitor PD-325901 or docetaxel revealed combinatorial activity. Given the high proportion of HNSCC patients with aberrations in the PI3K pathway and combinatorial activity observed, PF-384 with PD-901 or docetaxel merit further investigation in HNSCC. Supported by NIH Medical Research Scholars Program (SM, RVB, DFE) and NIDCD intramural projects ZIA-DC-000016, 73 and 74 (AS, JC, ZC, CVW). Citation Format: Suresh Mohan, Robert J. Vander Broek, Anthony D. Saleh, Matthew L. Pierce, Jamie F. Coupar, Danielle F. Eytan, Zhong Chen, Carter Van Waes. PI3K/mTOR dual inhibitor PF-5212384 inhibits aberrant NF-kB activation and exhibits activity in combination with MEK inhibitor PD-325901 and docetaxel in human head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2623. doi:10.1158/1538-7445.AM2014-2623
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