Abstract 836: ISU104, a fully human anti-ErbB3 antibody, overcomes acquired cetuximab resistance

Abstract ErbB3 is noted as one of major causes of acquired cetuximab resistance in colorectal and head and neck cancers. ErbB3 causes activation of alternative signaling pathways that bypass the original target and sustained PI3K/AKT activation, and these are associated with cetuximab resistance. We confirmed the induced ErbB3 activation by the cetuximab treatment in FaDu head and neck squamous-cell carcinoma (HNSCC) xenograft model. Immunoblot analysis was shown that twice weekly 10 mg/kg of cetuximab treatment upregulated ErbB3 expression and phosphorylation even though tumor growth was well controlled. To investigate whether ErbB3 activation by ligand, heregulin (HRG,) might induce cetuximab resistance, two cetuximab-sensitive colorectal cancer cell lines, DiFi and LIM1215, were treated 0-25 ng/mL of HRG. HRG induced dose-dependent cetuximab resistance in cell proliferation assay, and this was reversed via ISU104 treatment. To evaluate if ISU104 could overcome resistance to cetuximab in vivo, acquired cetuximab-resistant FaDu xenograft model was established. Tumors that had acquired resistance to 5 mg/kg of cetuximab treatment were significantly regressed by replaced treatment of ISU104 alone (10 mg/kg) or combination treatment of ISU104 and cetuximab, while mice continued on cetuximab only showed uncontrolled tumor growth like vehicle-treated group. Our results suggest that ISU104 effectively overcomes cetuximab resistance and may provide clinical benefit to cetuximab-resistant patients. Citation Format: Miyoung Kim, Youngmi Hur, Mirim Hong, Youngsoo Sohn, Kum-Joo Shin, Kyungyong Kim, Seung-Beom Hong, Kum-Joo Shin, Donggoo Bae. ISU104, a fully human anti-ErbB3 antibody, overcomes acquired cetuximab resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 836.