Targeting HER proteins in cancer therapy and the role of the non-target HER3

ArticleinBritish Journal of Cancer 97(4):453-7 · September 2007with5 Reads
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.
    • "This activation results in the propagation of a potent signaling cascade [18, 20, 23] and can also play a role in carcinogenesis [24, 25]. In addition, HER3 contains six binding sites for the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K) that are not present in EGFR or HER2, establishing HER3 as a strong intermediary for PI3K/AKT signaling [18, 26]. Here, we report on a novel V855A mutation located in exon 21 of the HER3 tyrosine kinase domain and found in the tumor specimen of an adolescent patient with a chemotherapy-resistant advanced NSCLC. "
    [Show abstract] [Hide abstract] ABSTRACT: Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3V855A somatic mutation homologous to the EGFRL858Ractivating mutation. Co-expression of HER3V855A and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.
    Full-text · Article · Dec 2015
    • "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. "
    [Show abstract] [Hide abstract] 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
    • "Consider a stress response network module, consisting of a stress-sensing transcriptional regulator and its stress-protective gene target, which has arisen in a cell's genome. Similar modules, such as Tn10 (Hillen & Berens, 1994), toxin-antitoxin systems (Yamaguchi et al, 2011), or bypass signaling (Hsieh & Moasser, 2007), can arise rapidly by recombination, horizontal gene transfer, or inhibitor-mediated alternate pathway activation. Considering their impact on microbial and cancer drug resistance, it is important to know how reproducibly and how quickly such stress defense networks can adapt (Lobkovsky & Koonin, 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Stress response genes and their regulators form networks that underlie drug resistance. These networks often have an inherent tradeoff: their expression is costly in the absence of stress, but beneficial in stress. They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two-component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with computational predictions, we find that: (i) intra-module mutations target and eliminate the module if it confers only cost without any benefit to the cell; (ii) intra- and extra-module mutations jointly activate the module if it is potentially beneficial and confers no cost; and (iii) a few specific mutations repeatedly fine-tune the module's noisy response if it has excessive costs and/or insufficient benefits. Overall, these findings reveal how the timing and mechanisms of stress response network evolution depend on the environment. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Aug 2015
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