Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs

Tejaswini P Reddy,Michael Kragh,Ivan D Horak,Roberto R Rosato,Johan Lantto,Wen Chen,Dong S Choi,Ann C Anselme,Jenny C Chang,Wei Qian

doi:10.1186/s13058-020-01280-z

Abstract

BackgroundThe human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. This study investigated the effects of Pan-HER (Symphogen, Ballerup, Denmark), a novel mixture of six monoclonal antibodies directed against members of the HER family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs).MethodsFifteen low passage TNBC PDX tumor samples were transferred into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 100–200 mm3, mice were randomized (n ≥ 6 per group) and treated following three 1-week cycles consisting of three times/week intraperitoneal (IP) injection of either formulation buffer (vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for Western blot, RNA, and immunohistochemistry analyses.ResultsAll 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor downmodulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways AKT and ERK. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation.ConclusionsThe marked effect of Pan-HER in numerous HER family-dependent TNBC PDX models justifies further studies of Pan-HER in TNBC clinical trials as a potential therapeutic option.

Highlights

The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy
The present study investigated the effects of Pan-HER, a novel mixture of six monoclonal antibodies directed against members of the human epidermal growth factor receptor (HER) family EGFR/HER1, human epidermal growth factor receptor 2 (HER2), and HER3 [4], in a preclinical trial of TNBC patient-derived xenografts (PDXs)
The potential therapeutic advantage of Pan-HER may reside in its ability to simultaneously target all three receptor tyrosine kinases (RTKs), which may in turn block, or at least significantly delay, the appearance of survival and escape mechanisms [4, 15]

Summary

Introduction

The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. Earlier studies, including clinical trials [11, 12], explore the concept of targeting simultaneously either HER family members or combining antibody-based therapy with kinase inhibitors [13, 14] and have set the stage for further investigation of this mechanistic-related concept In this context, the potential therapeutic advantage of Pan-HER may reside in its ability to simultaneously target all three receptor tyrosine kinases (RTKs), which may in turn block, or at least significantly delay, the appearance of survival and escape mechanisms [4, 15]

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Conclusion