Review
Resistance to human epidermal growth factor receptor type 2-targeted therapies

https://doi.org/10.1016/j.ejca.2014.01.003Get rights and content

Abstract

The overexpression of the human epidermal growth factor receptor type 2 (HER-2) is an independent prognostic factor of poor outcome in patients with breast cancer. Two compounds have been registered for HER-2-positive tumour treatment: trastuzumab, a humanised antibody directed against the HER-2 extracellular domain, and lapatinib, a small molecule acting as a dual EGF-R and HER-2 tyrosine kinase inhibitor. Although both drugs improve progression-free survival, many patients’ tumours will exhibit primary resistance, or develop secondary resistance, to anti-HER-2 therapies. The recent significant improvement of survival gained with pertuzumab (an antibody disrupting dimerisation of the receptor) or trastuzumab emtansine (T-DM1, a cytotoxic drug vectored by trastuzumab binding) opened the way for new registrations.

This review describes the molecular mechanisms by which tumour cells may adapt to and evade HER-2 inhibition by HER-2-targeted therapies and discusses strategies to prevent and overcome resistance to trastuzumab and lapatinib. These strategies may include the establishment of predictive markers, exploration of combination therapies and modulation of nodal targets.

Introduction

The human epidermal growth factor receptor type 2 (HER-2) is overexpressed in about 20% of invasive breast carcinomas and its gene amplification is associated with an increased metastatic potential and decreased overall survival [1]. As others HER family members (EGFR, HER-3 and HER-4), HER-2’s ectodomain consists of two IGF-like ligand-binding domains (I–III) and two cysteine-rich domains (II–IV) involved in the dimerisation process (Fig. 1). Noteworthy, HER-2 naturally displays a ligand-independent open conformation favouring its homo- or hetero-dimerisation. Consequently, transphosphorylation at the intracytoplasmic tyrosine kinase domain initiates a signal transduction through the MAPK and phosphoinositide 3-kinase (PI3K) pathways, which regulates cell proliferation, apoptosis, differentiation and migration. HER-3 is lacking the tyrosine kinase domain but is strongly associated with the p85 regulatory subunit of PI3K, and together with HER-2 or EGFR forms some highly active complexes.

Until recently, two compounds were registered in the metastatic setting, trastuzumab (Genentech, Roche), a humanised monoclonal antibody directed against HER-2 extracellular domain (ECD) [2], [3] and lapatinib (Glaxosmithkline), a dual intracellular tyrosine kinase inhibitor (TKI) that blocks HER-2 and EGFR activation [4]. However, despite the progresses brought by these drugs in the treatment of patients with HER-2-positive breast cancer, many cancers develop resistance. For instance, about 40% of HER-2-positive breast cancer patients may not respond to a first-line regimen including trastuzumab, and most of them will develop resistance within one year after initiation of trastuzumab treatment [2], [3]. The recent FDA’s approval of Pertuzumab (Genentech, Roche) and the survival benefit obtained with trastuzumab emtansine (t-DM1) [5] in trastuzumab-resistant metastatic breast cancer (MBC), reward long-term efforts in the understanding of molecular mechanisms of resistance to trastuzumab. This review outlines the molecular mechanisms by which tumour cells may adapt to and resist HER-2 inhibition. Based on identified mechanisms of resistance and the discovery of new predictive markers, new strategies may be developed to overcome it.

Section snippets

Mechanisms of resistance to anti-HER-2

Complex networks of intracellular signalling pathways are involved in HER-2 activation. Usually, resistance mechanisms are classified according to genetic or environmental alterations of receptors tyrosine kinase (RTKs) and their downstream effectors (de novo resistance) or the activation of alternative pathways, to by-pass the HER-2 inhibition after anti-HER-2 exposure (acquired resistance) [6]. Main clinical studies and current trials in trastuzumab-resistant MBC patients are summarised in

Designing the best strategy

The knowledge of these mechanisms of resistance has driven the development of new drugs or drugs combinations (Fig. 2). Their best use will require definition of predictive factors of resistance and rational sequences of treatment. The search for targetable nodes, common to multiple resistance pathways, is also appealing.

Take home message

De novo or acquired resistance to trastuzumab and lapatinib, for example those discovered in preclinical studies, may lead to therapeutic failure in the clinic. Currently, different strategies are being explored, such as maintaining the therapeutic pressure on the HER-2 pathway while targeting other key points of regulation (as exemplified by the drug sedimentation concept). Identification of node targets common to multiple resistance pathways should revolutionise our understanding and clinical

Conflict of interest statement

THERY Jean-Christophe: none SPANO Jean-Philippe: consultant for Roche, TEVA Pharma (Cephalon); member of advisory boards for Leopharma, Roche, GSK, Gilead, Pierre Fabre, Viphor and Merck Serono AZRIA David: member of scientific board of Roche; grant recipient from Roche for clinical trial. RAYMOND Eric: consultancies & Honoraria for GlaxoSmithKline PENAULT-LLORCA Frederique: consultancies & Honoraria for GlaxoSmithKline and Roche.

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