Abstract 2721: MEHD7945A, dual specific antibody against EGFR and HER3, augments radiation response in head and neck squamous cell carcinoma

Abstract

Abstract The HER receptor family members (EGFR, HER2, HER3 and HER4) play an important role in tumorigenesis. High EGFR expression levels correlate with poor prognosis and resistance to therapy for many epithelial tumors. Combining EGFR inhibition with radiation has been extensively studied in head and neck squamous cell carcinoma (HNSCC). Increasing evidence implicates HER3 as a key mediator of response and resistance to EGFR targeted therapies. We therefore examined the capacity of a dual specific antibody MEHD7945A, that can simultaneously target EGFR and HER3, to modulate radiation response in HNSCC. We characterized 10 HNSCC cell lines for their EGFR and HER3 expression. Immunoblot analysis confirmed that MEHD7945A significantly inhibited basal and radiation-induced EGFR and HER3 phosphorylation and downstream MAPK and AKT signaling. MEHD7945A consistently inhibited tumor cell growth in culture ranging from 30∼80%. The growth inhibitory effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibody alone. Using clonogenic survival assay, we found that MEHD7945A significantly enhanced radiosensitivity in HNSCC cells. Once again, this effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibodies. Treatment with MEHD7945A and radiation induced cell cycle arrest in G1 and G2 phases. Tumor cells eventually processed to apoptosis without successful DNA damage repair, as reflected by increased apoptotic populations detected by AnnexinV/PI staining. In addition, an increase of nuclear γ-H2AX foci was observed in cells receiving combination MEHD7945A and radiation. We administered MEHD7945A systemically to athymic mice bearing human tumor xenografts. Using single dose and fractionated radiation schedules, we observed that combined MEHD7945A and radiation was significantly more potent than single modality treatment to induce HNSCC tumor growth inhibition. These in vitro and in vivo results indicate that MEHD7945A can sensitize cells to radiation and inhibit HNSCC tumor growth, suggesting the potential of MEHD7945A as a radiation sensitizer for future clinical investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2721. doi:1538-7445.AM2012-2721