HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in Response to Anti-HER2 Herceptin in Breast Cancer

Merel Gijsen,Adrian L Harris,Anthony Kong,Peter J Parker,Banafshé Larijani,Peter King,Tim Perera,Christopher Kemp

doi:10.1371/journal.pbio.1000563

Abstract

Author SummaryHER2 (ErbB2) is a surface protein and member of the epidermal growth factor receptor (EGFR) family that is overexpressed in approximately one-fifth of breast cancers. HER2-positive breast tumours tend to be very aggressive, and patients with this type of tumour have a poor prognosis. A therapeutic monoclonal antibody called trastuzumab (Herceptin) has been designed to block HER2 signalling and is used as a treatment for patients with HER2-positive breast cancer. However, recent studies have shown that Herceptin does not decrease HER2 activation. This may be why patients invariably develop resistance if treated with Herceptin monotherapy. To date, no study has explained why Herceptin cannot abolish HER2 signalling despite being an anti-HER2 monoclonal antibody. We have found that Herceptin switches on a feedback loop that increases the production of the ADAM17 protein, a protease that in turn releases the growth factors that activate HER (ErbB) receptors. These growth factors activate HER2 and also the other members of the HER receptor family—EGFR, HER3 and HER4—in such a way as to maintain HER2 activation and cell survival in HER2-positive breast cancer cells. We have found that when Herceptin is provided in combination with ADAM17 inhibitors, the feedback loop is abrogated in cells. Furthermore, a pan-HER inhibitor that decreases the activation of other HER receptors can also inhibit the feedback loop and decrease HER2 activation when used in combination with Herceptin. We further demonstrated that the combination therapy of Herceptin with a pan-HER inhibitor is more effective than Herceptin alone in an animal model of breast cancer. We believe our results offer treatment strategies that may help overcome acquired Herceptin resistance in patients with HER2-positive breast cancer.

Highlights

Dysregulation of human epidermal growth factor (HER/ErbB) receptors is implicated in various epithelial cancers [1]
HER2 (ErbB2) is a surface protein and member of the epidermal growth factor receptor (EGFR) family that is overexpressed in approximately one-fifth of breast cancers
We have found that Herceptin switches on a feedback loop that increases the production of the ADAM17 protein, a protease that in turn releases the growth factors that activate HER (ErbB) receptors

Summary

Introduction

Dysregulation of human epidermal growth factor (HER/ErbB) receptors is implicated in various epithelial cancers [1]. The ligand-induced HER receptor dimerisation follows a strict hierarchy, and HER2 has been shown to be the preferred dimerisation partner [3]. The crystal structure explains why HER2 is ligandless, since its extracellular domain is always in the ‘‘open’’ conformation, with the projection of domain II ready for dimerisation even when monomeric [4]. This fixed ‘‘open’’ conformation of HER2 in the absence of ligand binding (mimicking the ligand-bound form in the EGFR structure) may account for why it is the preferred dimerisation partner [3]

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