Abstract 637: MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR inhibitors in head and neck and lung tumors

Abstract The development of acquired resistance to EGFR inhibitors is emerging as a potential treatment barrier for EGFR targeted therapies. Efforts to better understand underlying mechanisms of acquired resistance to EGFR inhibitors, and strategies to overcome this resistance are highly desired. We have previously identified that acquired resistance to EGFR inhibitors may result from the trans-activation of ErbB3 by EGFR. We therefore examined the capacity of the EGFR/ErbB3 dual specific antibody, MEHD7945A to overcome acquired resistance to EGFR inhibitors. We first examined the antiproliferative effects of MEHD7945A across a panel of human head and neck (HNSCC) and non-small cell lung (NSCLC) tumor cell lines. MEHD7945A significantly inhibited the proliferation in tumors cells that express EGFR and ErbB3. We then applied MEHD7945A to EGFR inhibitor-resistant clones from HNSCC (SCC-1 and SCC-6) and NSCLC lines (H226) that have been chronically exposed to cetuximab or erlotinib and show EGFR inhibitor-resistant phenotypes. Using identical doses of MEHD7945A and cetuximab, we found that MEHD7945A inhibited the growth of tumor cells that exhibit resistance to cetuximab. Similar results were observed in our erlotinib-resistant clones. MEHD7945A also significantly inhibited EGFR and ErbB3-dependent downstream signaling. Additional studies to confirm the antitumor activity of MEHD7945A in xenograft models using EGFR inhibitor-resistant clones are in progress. In addition, studies to investigate the impact of MEHD7945A on radiation response profiles in a panel of HNSCC, NSCLC and EGFR-inhibitor resistant cell lines are underway. These data not only support an important role of ErbB3 in acquired resistance to EGFR inhibitors but also suggest MEHD7945A may provide a valuable treatment strategy for patients who develop acquired resistance to EGFR targeting agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2011-637