Abstract 657: Simultaneous inhibition of HER-family receptors by Pan-HER antibody mixture prevents compensatory HER-family receptor upregulation and induces cell death in a broad range of tumor models

Abstract

Abstract Deregulation of HER family receptors plays an important role in the development and progression of human cancer. Although EGFR and HER2 receptors have proven to be clinically valuable targets, increasing evidence suggests substantial cross-talk between HER family members, and thus compensatory signaling may lead to resistance upon therapies targeting one receptor only. Targeting multiple receptors is more efficacious than single-targeted therapies, and is frequently able to overcome acquired resistance to inhibition of a single receptor. We have previously demonstrated that Pan-HER (Sym013) a mixture of monoclonal antibodies specifically targeting EGFR, HER2, and HER3 displays potent growth inhibition in a broad range of cancer cell lines. Growth-inhibiting activity persisted in the presence of EGFR and HER3 ligands, indicating that Pan-HER may overcome acquired resistance due to increased ligand production. In vitro findings further translated into in vivo model systems, where Pan-HER displayed efficacious tumor growth suppression across a broad range of cancer models, including KRAS-mutated patient-derived pancreatic cancer models, and was frequently able to overcome resistance to other HER family targeted therapies. Mechanistic studies confirm that Pan-HER treatment significantly decreases viability and induces apoptosis more effectively than single-receptor targeted therapies. Pan-HER treatment induces internalization and degradation of all three receptors in vitro, followed by subsequent downstream effects in essential growth and survival pathways. Compensatory receptor up-regulation and/or activation is frequently the downside of single-receptor targeted treatments. However, such receptor up-regulation is effectively prevented by Pan-HER. Histological assessment of Pan-HER-treated patient-derived xenograft tumors revealed that they largely consist of stromal cells, whereas tumor cells are sparse. Further immunohistochemical staining has also shown that these tumors have markedly lower EGFR, HER2, and HER3 receptor expression than tumors treated with single-receptor targeting regimens. We present here further evidence of Pan-HER superiority over single-receptor targeted regimens. Overall, Pan-HER represents a novel strategy to address tumor heterogeneity andtumor plasticity. Citation Format: Anna Dahlman, Helle J. Jacobsen, Thomas T. Poulsen, Paolo Conrotto, Mikkel W. Pedersen, Ivan D. Horak, Michael Kragh, Johan Lantto. Simultaneous inhibition of HER-family receptors by Pan-HER antibody mixture prevents compensatory HER-family receptor upregulation and induces cell death in a broad range of tumor 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 657. doi:10.1158/1538-7445.AM2014-657