Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma

Nathan Redlich,Douglas R Adkins,Anthony M Robinson,Randall J Kimple,Brian A Van Tine,Kwangok P Nickel,Loren S Michel,Deric L Wheeler,Andrew P Stein,Ravindra Uppaluri

doi:10.1038/s41419-017-0029-0

Abstract

ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.

Highlights

Head and neck squamous cell cancer (HNSCC) is a collection of diseases arising from the mucosal surfaces of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx
In this report we use a panel of patientderived xenograft models (PDX) and their cellular derivatives to show that ErbB3 is an essential component of the tumor growth machinery in HNSCC
HNSCC is widely considered to be an Epidermal growth factor receptor (EGFR)-driven disease as its overexpression confers a poor prognosis[39], Cetuximab is active in this disease, and most cell lines and many PDX models are sensitive to the growth inhibitory properties of cetuximab[40]

Summary

Introduction

Head and neck squamous cell cancer (HNSCC) is a collection of diseases arising from the mucosal surfaces of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Tobacco smoke produces a significant mutational burden in smoking related cancers such as HNSCC and other aerodigestive tumors, and is presumed to be responsible for transformation[4,5,6]. Similar to other smoking related tumors, HNSCC sequencing efforts have revealed that mutations are often scattered throughout the genome, and the number of high-. The other ErbB family members are thought to be involved in HNSCC but only preliminary in vivo investigations of family targeting have been reported[14,15]. ErbB2 (aka HER2) is amplified in HNSCC at a very low frequency and ErbB3 (aka HER3), the kinase-dead member of the family, is neither mutated nor amplified in this disease[11].

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