Abstract 1818: ERBB3/HER2 signaling limits the effectiveness of EGFR blockade in head and neck and colorectal cancer models

Abstract

Abstract Introduction: EGFR blocking antibodies are approved for the treatment of colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC). However, responses to single agent EGFR blocking antibodies are relatively infrequent and transient. Thus, there is a clear need for agents that can enhance the benefit of EGFR blockade. While ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. In this report, we employ blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955), as well as a HER2 blocking antibody, to investigate the role of ERBB3 in modulating the response to EGFR inhibition. Experimental procedures and results: We show that EGFR and ERBB3 are co-activated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits the growth of these cell lines more effectively than blockade of either receptor alone. Western blotting analysis shows that REGN955 strongly inhibits activation of ERK, but not Akt, while REGN1400 strongly inhibits activation of Akt, but not ERK, consistent with the more potent effect of the combination on cell growth. In addition, using a colorectal cancer cell line with low endogenous ERBB3 activity, we show that neuregulin 1 treatment significantly increases ERBB3 phosphorylation and reverses the inhibitory effect of REGN955 on cell growth. To further understand the mechanism of ERBB3 activation, we employed a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and CRC cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on CRC cell growth. Finally, while REGN1400 and REGN955 as single agents slowed the growth of HNSCC and CRC xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Summary and conclusion: Our findings demonstrate that ERBB3 partners with HER2 to activate the Akt survival pathway and to limit the effect of EGFR blockade on the growth of HNSCC and CRC cell lines and tumor xenografts. These findings suggest that REGN1400, which is currently in a Phase 1 clinical trial, could provide clinical benefit when combined with EGFR blocking antibodies. Citation Format: Li Zhang, Carla Castanaro, Bo Luan, Katie Yang, Amy Fan, John Rudge, Nicholas Papadopoulos, Gavin Thurston, Christopher Daly. ERBB3/HER2 signaling limits the effectiveness of EGFR blockade in head and neck and colorectal cancer models. [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 1818. doi:10.1158/1538-7445.AM2014-1818