Targeting the function of the HER2 oncogene in human cancer therapeutics

Moasser, Mark M.

doi:10.1038/sj.onc.1210478

Cited by 178 publications

(145 citation statements)

References 129 publications

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“…Trastuzumab is widely used in the treatment of ErbB2-amplified breast cancer where it causes tumor regression in 11 -26 % of patients with metastatic disease and increases disease-free survival when used with traditional chemotherapy in early stage disease [163][164][165]. Our understanding of ErbB2 signaling has evolved since the development of trastuzumab, and interference with ligand binding or the induction of receptor endocytosis and degradation are unlikely mechanisms of inhibition in the case of trastuzumab and ErbB2 [166]. The clinical anti-cancer activity of trastuzumab has generated efforts to determine its mechanism of action but no compelling mechanism has yet emerged.…”

Section: Targeted Therapymentioning

confidence: 99%

“…Importantly, MET inhibition restores gefitinib sensitivity acting as a model for future therapies aimed at overcoming TKI resistance due to ErbB3 transactivation. Similarly, breast cancers containing amplified ErbB2 would be expected to respond to TKIs directed at ErbB2, but clinical studies show widespread resistance to TKI therapy in this disease [166]. This appears to be due to the failure of TKIs to effectively suppress ErbB3 signaling in these tumors due to Akt-driven negative feedback signaling loops [47].…”

Section: Resistance To Targeted Therapymentioning

confidence: 99%

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The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

629

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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Section: Targeted Therapymentioning

confidence: 99%

Section: Resistance To Targeted Therapymentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

629

503

View full text Add to dashboard Cite

show abstract

“…Understanding resistance to trastuzumab has been a challenging problem, and this is largely due to the fact that the mechanisms of response to trastuzumab are not well understood. Trastuzumab binds to the extracellular domain of HER2, but extensive efforts have not been able to determine how and whether this suppresses oncogenic HER2 function (reviewed in Moasser, 2007b). Immunologic targeting may play a significant part in the mechanism of action of trastuzumab.…”

Section: Targeting Her Proteins In Breast Cancermentioning

confidence: 99%

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

2007

Self Cite

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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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“…HER2 is a member of the HER (EGFR/ErbB) receptor family encompassing the 4 HER receptors (HER1-HER4) that are involved in signal transduction (1). Each of these receptors contains an extracellular, a trans-membrane, and an intracellular domain.…”

Section: Introductionmentioning

confidence: 99%

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

Ludyga

Anastasov

Rosemann

et al. 2013

Molecular Cancer Research

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Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co-and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer.

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Targeting the function of the HER2 oncogene in human cancer therapeutics

Cited by 178 publications

References 129 publications

The epidermal growth factor receptor family: Biology driving targeted therapeutics

The epidermal growth factor receptor family: Biology driving targeted therapeutics

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

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

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