c-erbB-2, a Tyrosine Kinase Growth Factor Receptor and its Role in Breast Cancer

1992 ◽  
pp. 23-40 ◽  
Author(s):  
F. J. Lofts ◽  
W. J. Gullick
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer

2011 ◽  
Vol 7 (5) ◽  
pp. 1603 ◽  
Author(s):  
Natalie Ludyga ◽  
Nataša Anastasov ◽  
Iria Gonzalez-Vasconcellos ◽  
Manuela Ram ◽  
Heinz Höfler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Protein Tyrosine ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

Overview of tyrosine kinase inhibitors in clinical breast cancer

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S135-S144 ◽  
Author(s):  
A Agrawal ◽  
E Gutteridge ◽  
J M W Gee ◽  
R I Nicholson ◽  
J F R Robertson
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Cancer Trial ◽  
Er Positive ◽  
Clinical Breast

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.

scholarly journals Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers

Antibodies ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 7
Author(s):  
Jun Zhao ◽  
Nishant Mohan ◽  
Ruth Nussinov ◽  
Buyong Ma ◽  
Wen Jin Wu
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Domain ◽  
Her Family ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerization of HER2 in HER2-overexpressing breast cancer cells, which attenuates HER2-mediated signaling. Trastuzumab binds to the domain IV of the HER2 extracellular domain and does not directly block the dimerization interface of HER2-HER2 molecules. The three-dimensional structures of the tyrosine kinase domains of ErbB/HER family receptors show asymmetrical packing of the two monomers with distinct conformations. One monomer functions as an activator, whereas the other acts as a receiver. Once activated, the receiver monomer phosphorylates the activator or other proteins. Interestingly, in our previous work, we found that the binding of trastuzumab induced phosphorylation of HER2 with the phosphorylation pattern of HER2 that is different from that mediated by epidermal growth factor (EGF) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Binding of trastuzumab to HER2 promoted an allosteric effect of HER2, in both tyrosine kinase domain and ectodomain of HER2 although details of allosteric regulation were missing. In this study, we utilized molecular dynamics (MD) simulations to model the allosteric consequences of trastuzumab binding to HER2 homodimers and heterodimers, along with the apo forms as controls. We focused on the conformational changes of HER2 in its monomeric and dimeric forms. The data indicated the apparent dual role of trastuzumab as an antagonist and an agonist. The molecular details of the simulation provide an atomic level description and molecular insight into the action of HER2-targeted antibody therapeutics.

scholarly journals Studies of epidermal growth factor receptor inhibition in breast cancer.

2001 ◽  
pp. 183-189 ◽  
Author(s):  
N J Bundred ◽  
K Chan ◽  
N G Anderson
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Type I ◽  
Epidermal Growth ◽  
Xenograft Models ◽  
Egfr Tkis

Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.

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