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


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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    • "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.
    Pharmacological reviews 10/2014; 66(4):918-47. DOI:10.1124/pr.114.008862 · 17.10 Impact Factor
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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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    Frontiers in Oncology 08/2014; 4:204. DOI:10.3389/fonc.2014.00204
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    • "EGF is a preferable ligand for EGFR/EGFR homodimer or EGFR/HER2 heterodimer, while heregulin-α is a preferable ligand for HER2/HER3 heterodimer (26,27). HER2 has no ligand and HER3 has no tyrosine kinase activity, and they play their function by forming heterodimers with other HER receptors. "
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    ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2‑IIa. sPLA2‑IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2‑PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose‑dependent manner in lung cancer cells. The structure and sequence‑based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2‑IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2‑IIa is a potential therapeutic target against lung cancer.
    International Journal of Oncology 06/2014; 45(3). DOI:10.3892/ijo.2014.2486 · 3.03 Impact Factor
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