ReviewResistance to human epidermal growth factor receptor type 2-targeted therapies
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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The Effects of HER2 on CDK4/6 Activity in Breast Cancer
2022, Clinical Breast CancerCitation Excerpt :Unfortunately, HER2 overexpression is associated with decreased disease-free survival, and overall survival.22 Anti–HER2 drugs such as trastuzumab have shown to improve the prognosis of women with HER2+ breast cancer23-25; however, resistance to HER2-targeted therapies may develop.26 In mouse models, it has been demonstrated that the resistance is conferred by the cyclin D1-CDK4 pathway, and CDK4/6 inhibitors can re-sensitize tumor cells to HER2-targeted therapies.27
Recent advances in HER2-targeted delivery for cancer therapy
2021, Drug Discovery TodayCitation Excerpt :Despite substantial progress in the development and use of HER2-targeted therapy, intrinsic and acquired resistance are major challenges in the clinic [8,9]. Investigations to understand the mechanisms of resistance have demonstrated numerous factors, such as upregulation of downstream effectors, impaired binding of therapeutic agents to HER2, alteration of tyrosine kinase receptors, and/or activation of alternative pathways, by which tumor cells can compensate for or evade inhibition of HER2 signaling [8,10]. By contrast, the overexpression of HER2 receptors on cancer cells has also attracted drug delivery researchers to target this receptor via ligand targeted approach (active targeting).
Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial
2020, The Lancet OncologyCitation Excerpt :More recent advances include the dimerisation inhibitor pertuzumab and the antibody drug conjugate trastuzumab emtansine.5 Unfortunately, multiple mechanisms of resistance are known to emerge against HER2-targeted therapies, notably those mediated by effectors downstream of the HER2 receptor.6 International guidelines recommend that patients whose tumours progress on an anti-HER2 therapy in combination with a cytotoxic or endocrine agent should be offered additional anti-HER2 agents to achieve ongoing suppression of HER2 pathway signalling.7
Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE
2020, Toxicology LettersCitation Excerpt :It plays a therapeutic role by reducing the activation of signaling pathways caused by ligand binding, reducing the number of HER2 by intracellular drinks, as well as utilizing the function of Fc segment of IgG1(Yamauchi et al., 2011). However, a significant proportion of patients may develop resistance within one year after trastuzumab treatment (Thery et al., 2014). Previously conducted clinical trials have demonstrated that ADCs notably improved clinical effects compared with antibodies alone for the same target.
The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer
2016, Cancer LettersCitation Excerpt :Thus, there is an urgent need to develop new therapeutic strategies that could overcome the limited efficacy of trastuzumab. There are many proposed mechanisms underlying trastuzumab resistance [4]. Recent studies have shown that the activation of HER3 signaling plays a significant role in HER2-positive GC [5,6].