Abstract LB-216: Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.LB-216-LB-216
• Main Authors: Calvert, Valerie S., Fröhlich, Camilla, Poulsen, Thomas T., Pedersen, Mikkel W., Kragh, Michael, Horak, Ivan D., Petricoin, Emanuel F.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-LB-216

Plasticity of the ErbB family of receptors and ligands is a hallmark of many human tumors and drives resistance to EGFR and HER2 targeting agents such as cetuximab or trastuzumab. Pan-HER is a unique antibody mixture designed to counter ErbB family plasticity by simultaneously targeting EGFR, HER2 and HER3. Pan-HER contains pairs of antibodies against each of the receptors, six antibodies in total, and induces efficient internalization and degradation of all three receptors. Here, the anti-tumor activity of Pan-HER was investigated in a panel of 57 patient-derived epithelial tumor models (PDXs) of various origin including pancreatic (18), colorectal (11), triple negative breast (11), lung (6), squamous head and neck (6), ovarian (3), and gastric (2) cancer, and the level of activity was correlated to baseline protein and phosphoprotein status using laser capture microdissection (LCM) and Reverse Phase Protein Arrays (RPPA). This panel has been preselected to represent hard-to-treat cancers and that are not overtly HER family positive. Pan-HER demonstrated anti-tumor activity across all indications except the gastric models and induced tumor regression in 26 of the 57 PDX models tested. The LCM-RPPA analysis of over 150 proteins and phosphoproteins that are known to be central for receptor tyrosine kinase signaling, survival, apoptosis, growth, inflammation, motility and autophagy identified both broad and indication specific signatures of response to Pan-HER and points to a key role for the KRAS/BRAF/ERK and PIK3CA/AKT pathway activation that associate with therapeutic sensitivity. In conclusion, our results demonstrate that Pan-HER has broad anti-tumor activity across indications and identify phosphoprotein pathway activation signatures predicting for sensitivity or resistance that should be explored clinically. Citation Format: Valerie S. Calvert, Camilla Fröhlich, Thomas T. Poulsen, Mikkel W. Pedersen, Michael Kragh, Ivan D. Horak, Emanuel F. Petricoin. Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting [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 LB-216.