Abstract 2615: Dual ErbB blockade with KTN3379 and cetuximab yields enhanced antitumor activity by inhibiting parallel signaling pathways in SCCHN

The receptor tyrosine kinase ErbB3/HER3 has been implicated as an oncogenic driver in pre-clinical models of solid tumors, and is the target of several monoclonal antibodies currently in clinical development. In squamous cell carcinoma of the head and neck (SCCHN), ErbB3 activation is regulated by its ligand neuregulin (NRG). Studies, including our own, have reported high NRG expression in a significant subset of SCCHN, providing a scientific rationale for the use of ErbB3 targeted therapies in this disease setting. Here we show that KTN3379, a potent human ErbB3 monoclonal antibody with a dual mechanism of action, demonstrates significant monotherapy activity in NRG expressing xenograft models of SCCHN and enhances cetuximab anti-tumor activity. Using a panel of SCCHN cell lines, we demonstrate that KTN3379 inhibits PI3K/AKT signaling whereas cetuximab chiefly suppresses the ERK pathway, providing an explanation for the increased anti-tumor activity of combining both drugs. Our data also suggest that ErbB3 and EGFR act independently of one another at the receptor level. Interestingly, mRNA analysis of 303 SCCHN human tumor samples shows a strong correlation between NRG expression and the EGFR ligands Amphiregulin (AREG) and TGFα. Moreover, KTN3379 activity correlates with expression of ErbB3, its ligand NRG, and both of these EGFR ligands. Overall, our data support evaluation of the combination of KTN3379 and cetuximab in SCCHN. Citation Format: Diego Alvarado, Scott B. Seibel, Gwenda F. Ligon, Jay S. Lillquist, Andrew Pierce, Richard Gedrich, Theresa M. LaVallee. Dual ErbB blockade with KTN3379 and cetuximab yields enhanced antitumor activity by inhibiting parallel signaling pathways in SCCHN. [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 2615. doi:10.1158/1538-7445.AM2015-2615