Abstract
Abstract Background: The phosphoinositide 3-kinase (PI3K) pathway is thought to be the most frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by deregulated receptors such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this investigation, we use blocking antibodies against HER3 and its ligand, neuregulin β-1, (KTN3379) and PIK3CA (BYL719) to investigate the effect of HER3 in modulating response to PI3K inhibition. Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects, and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibits the growth of HNSCC cell lines more effectively than inhibition of a single receptor alone, in both cell proliferation and colony formation assays. Combined treatment decreases phosphorylation of AKT and S6 more effectively than inhibition with either drug in some HNSCC cell lines. Treatment with neuregulin β-1 diminishes the inhibitory effect of BYL719 on HNSCC cell growth. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 pathway in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K resistance. Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade leads to pronounced effects in pre-clinical models of HNSCC. These findings suggest that HER3 blockade, may be efficacious when combined with PI3K pathway inhibition. Citation Format: Kara S. Davis, Nayel Khan, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2015-1674
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