Article

Hsieh AC, Moasser MM.. Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97: 453-457

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
British Journal of Cancer (Impact Factor: 4.84). 09/2007; 97(4):453-7. DOI: 10.1038/sj.bjc.6603910
Source: PubMed

ABSTRACT

Members of the human epidermal growth factor receptor (HER) family have been of considerable interest in the cancer arena due to their potential to induce tumorigenesis when their signalling functions are deregulated. The constitutive activation of these proteins is seen in a number of different common cancer subtypes, and in particular EGFR and HER2 have become highly pursued targets for anti-cancer drug development. Clinical studies in a number of different cancers known to be driven by EGFR or HER2 show mixed results, and further mechanistic understanding of drug sensitivity and resistance is needed to realise the full potential of this treatment modality. Signalling in trans is a key feature of HER family signalling, and the activation of the PI3K/Akt pathway, so critically important in tumorigenesis, is driven predominantly through phosphorylation in trans of the kinase inactive member HER3. An increasing body of evidence shows that HER3 plays a critical role in EGFR- and HER2-driven tumours. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signalling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness. Since HER3 is kinase inactive, it is not a direct target of kinase inhibitors and not presently an easily drugable target. This review presents the current evidence highlighting the role of HER3 in tumorigenesis and its role in mediating resistance to inhibitors of EGFR and HER2.

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    • "This family is involved in epithelial cell differentiation , growth, division and motility, and alteration or disruption of their function plays important roles in the development and progression of malignancy[2,3]. HER3 is unique among the family members because it contains a truncated intracytoplasmic domain that is deficient in TK activity456and depends on heterodimer formation, usually with HER2, to mediate its signaling activity[7,8]. HER3 is overexpressed in many carcinomas, including colorectal cancer (CRC), which is associated with poor prognosis[9,10], making it a target of cancer therapy and diagnosis. "
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    ABSTRACT: HER3 is overexpressed in various carcinomas including colorectal cancer (CRC), which is associated with poor prognosis, and is involved in the development of therapy resistance. Thus, an in vivo imaging technique is needed to evaluate the expression of HER3, an important therapeutic and diagnostic target. Here, we report successful HER3 PET imaging using a newly generated anti-human HER3 monoclonal antibody, Mab#58, and a mouse model of a HER3-overexpressing xenograft tumor. Furthermore, we assessed the role of HER3 signaling in CRC cancer tissue-originated spheroid (CTOS) and applied HER3 imaging to detect endogenous HER3 in CTOS-derived xenografts. Cell binding assays of 89Zr-labeled Mab#58 using the HER3-overexpressing cell line HER3/RH7777 demonstrated that [89Zr]Mab#58 specifically bound to HER3/RH7777 cells (Kd = 2.7 nM). In vivo biodistribution study in mice bearing HER3/RH7777 and its parent cell xenografts showed that tumor accumulation of [89Zr]Mab#58 in HER3/RH7777 xenografts was significantly higher than that in the control from day 1 to day 4, tending to increase from day 1 to day 4 and reaching 12.2 ± 4.5%ID/g. Radioactivity in other tissues, including the control xenograft, decreased or remained unchanged from day 1 to day 6. Positron emission tomography (PET) in the same model enabled clear visualization of HER3/RH7777 xenografts but not of RH7777 xenografts. CTOS growth assay and signaling assay revealed that CRC CTOS were dependent on HER3 signaling for their growth. In PET studies of mice bearing a CRC CTOS xenograft, the tumor was clearly visualized with [89Zr]Mab#58 but not with the 89Zr-labeled control antibody. Thus, tumor expression of HER3 was successfully visualized by PET with 89Zr-labeled anti-HER3 antibody in CTOS xenograft-bearing mice, a model that retains the properties of the patient tumor. Non-invasive targeting of HER3 by antibodies is feasible, and it is expected to be useful for cancer diagnosis and treatment.
    Full-text · Article · Nov 2015 · PLoS ONE
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    • "In addition, trastuzumab inhibits HER2/neu extracellular domain cleavage in breast cancer cells, a process that contributes to the unregulated growth observed in this cancer (Albanell et al., 2003), and also mediates antibody-dependent cell cytotoxicity. By contrast, pertuzumab binds to subdomain II of the HER2/ neu receptor and blocks ligand-dependent HER2 heterodimerization with HER1, HER3, and HER4, while also mediating antibody-dependent cell toxicity (Hynes and Lane, 2005; Hsieh and Moasser, 2007). Importantly, by targeting different domains on the HER2 receptor, pertuzumab and trastuzumab can be administered in combination to provide a more comprehensive blockade of HER2-driven signaling pathways (Scheuer et al., 2009). "
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    ABSTRACT: Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.
    Full-text · Article · Oct 2014 · Pharmacological reviews
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    • "The epidermal growth factor receptor family (ERBB family) comprises four tyrosine kinase receptors: HER-1 (EGFR), HER-2/neu (ERBB2), HER-3 (ERBB3), and HER-4 (ERBB4) (38, 39). Following ligand-binding, EGFR receptors homo- and hetero-dimerize and promote autophosphorylation of the intracellular tyrosine kinase domain and initiate molecular cascade of events involved in growth, cell proliferation, differentiation, and survival (10, 11, 40). "
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    ABSTRACT: Lung cancer remains the most lethal malignancy in the world. Despite improvements in surgical treatment, systemic therapy, and radiotherapy, the 5-year survival rate for all patients diagnosed with lung cancer remains between 15 and 20%. Newer therapeutic strategies rely on specific molecular alterations, or biomarkers, that provide opportunities for a personalized approach to specific patient populations. Classification of lung cancer is becoming increasingly focused on these biomarkers, which renders the term "non-small cell lung" cancer less clinically useful. Non-small cell lung cancer is now recognized as a complex malignancy and its molecular and genomic diversity allows for patient-centered treatment options. Here, we review advances in targeted treatment of lung adenocarcinoma with respect to five clinically relevant biomarkers - EGFR, ALK, MET, ROS-1, and KRAS.
    Full-text · Article · Aug 2014 · Frontiers in Oncology
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