Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth.

By D. Agus, R. Akita, W. Fox, G. Lewis, B. Higgins, P. Pisacane, J. Lofgren, C. Tindell, Douglas P. Evans, K. Maiese and 2 more. Cancer Cell, 2002

910 citations recorded by the source corpus.

ErbB2 is a ligand-less member of the ErbB receptor family that functions as a coreceptor with EGFR, ErbB3, and ErbB4. Here, we describe an approach to target ErbB2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders ErbB2's recruitment into ErbB ligand complexes. Inhibition of ligand-dependent ErbB2 signaling by 2C4 occurs in both low- and high-ErbB2-expressing systems. Since the ErbB3 receptor contains an inactive tyrosine kinase domain, 2C4 is very effective in blocking heregulin-mediated ErbB3-ErbB2 signaling. We demonstrate that the in vitro and in vivo growth of several breast and prostate tumor models is inhibited by 2C4 treatment.

Subfields: Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/e88ae620d31e80450a6bd138dbc9a0133b380317

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. N. Hynes
2. J. Baselga
3. M. Aglietta
4. G. Valabrega
5. F. Montemurro
6. Carlos L. Arteaga
7. R. Nahta
8. Thomas Holbro

In Radiology, Nuclear Medicine and Imaging

1. N. Hynes
2. J. Baselga
3. M. Aglietta
4. G. Valabrega
5. F. Montemurro
6. R. Nahta
7. Thomas Holbro
8. Carlos L. Arteaga

Citations in the corpus

• Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. (2009, methodology): “, 2004) efficiently blocks ligand-induced HER2/HER3 dimerization (Agus et al., 2002).”
• The discovery of receptor tyrosine kinases: targets for cancer therapy (2004, background): “It is now in Phase II clinical trials and represents a second generation of anti-HER2 monoclonal antibodies that interfere with the mechanism of oncogenic signal generation by HER2–HER3 heterodimer”
• Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. (2009, background): “Pertuzumab prevents the HER2 protein from dimerizing with HER3 and/or HER1 (26, 27, 29, 43), thus blocking these potential escape pathways.”
• Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. (2004, background): “hkl |F(obs)| |F(calc)| / hkl |F(obs)| fragment of pertuzumab, which will not cause antibody-depenNAG -D-N-acetylglucosamine; man -D-mannose dent cytotoxicity, appears to be just as effective as the intact MAb at inhibiting ErbB2-mediated signaling, in contrast to the ineffectiveness of the trastuzum”
• Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. (2010, background): “Thus, pertuzumab is a potent inhibitor of HER-mediated signaling(12,13) and has demonstrated excellent activity against several HER2-dependent breast cancer cell lines.(13) Pertuzumab inhibits HER2 signaling by binding to a different HER2 epitope than trastuzumab, and the addition of pertuzumab afte”
• ErbB receptors: directing key signaling networks throughout life. (2004, background): “Further evidence pointing to the importance of ErbB2 heterodimers in tumor cells comes from xenograft studies, where it was shown that administration of the ErbB2-directed mAb 2C4, which prevents the receptor from heterodimerizing, results in potent antitumor effects, in some instances better than H”
• The HER-2-Targeting Antibodies Trastuzumab and Pertuzumab Synergistically Inhibit the Survival of Breast Cancer Cells (2004, background): “Because total EGFR and HER-3 levels did not change on treatment with the drugs, these data suggest that trastuzumab increases the ability of pertuzumab to disrupt HER-2 receptor dimers.”
• Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer (2006, background): “The recombinant humanized HER2 monoclonal antibody pertuzumab (also known as 2C4 or Omnitarg ® , Genentech, San Francisco, CA) sterically blocks dimerization of HER2 with EGFR and HER3”
• Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. (2005, background): “Pertuzumab has been shown to block dimerization between HER-2 and EGFR or HER-3 (15).”
• ERBB receptors and cancer: the complexity of targeted inhibitors (2005, background): “, and it cannot prevent the ligand-induced formation of ERBB2-containing heterodimers or the activation of downstream signalling pathway”