Abstract 2979: Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC

Abstract

Abstract Background: The phosphoinositide 3-kinase (PI3K) pathway is a frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by dysregulation of receptor tyrosine kinases, 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 study, we use the human monoclonal antibody KTN3379, which blocks HER3 in the autoinhibited configuration and thus inhibits ligand-independent and ligand, neuregulin β-1,-dependent HER3 activation, and an inhibitor of PIK3CA (BYL719) to determine if HER3 and PIK3CA can be inhibited in a synergistic fashion. KTN3379 and BYL719 are clinical stage compounds and are being evaluated in HNSCC clinical trials. Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC cell lines, 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) inhibited the growth of HNSCC cell lines in a synergistic fashion (CI range 0.1-0.5), in both cell proliferation and colony formation assays. This synergy appeared to be less pronounced in HPV-associated cancer cell lines. Combined treatment decreased tumor growth in xenograft models of HNSCC. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 protein in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K pathway inhibitor resistance. Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade has synergistic effects in pre-clinical HNSCC models. These findings suggest that HER3 and PI3K dual inhibition may be more effective in tumors that are resistant to mono-therapy with either HER3 or PI3K inhibition alone. Citation Format: Nayel Khan, Kara S. Davis, Neal Godse, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2979.