The EGF receptor family as targets for cancer therapy

Abstract

Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments. In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and`chimeric' and`humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation therapy and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer. Oncogene (2000) 19, 6550 ± 6565.

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

“…5 Cetuximab (Erbitux; Merck KgaA, Darmstadt, Germany) is an immunoglobulin G1 monoclonal antibody that specifically targets EGFR, competitively inhibiting ligand binding and ligand-dependent downstream signaling. 6 Phase 1 clinical trials demonstrated the safety of cetuximab combined with CP 7 and cetuximab combined with radiation therapy 8 in SCCs other than anal carcinoma. Also, in phase 3 clinical trials, adding cetuximab to first-line chemotherapy or RT improves outcomes in various types of cancers.…”

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

“…ErbB1 and ErbB2 are well-established oncogenes and cancer drug targets. They are implicated in the pathogenesis of various epithelial and neural malignancies, and their overactivity is associated with poor patient outcome (Slamon et al, 1987;Mendelsohn and Baselga, 2000;Hynes and Lane, 2005). Targeted therapeutics including both monoclonal antibodies and small-molecular-weight kinase inhibitors blocking the functions of ErbB1 and/or ErbB2 have demonstrated therapeutic effect in clinical trials.…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…Epidermal growth factor (EGF) and its family members (e.g., transforming growth factor-a) affect cell growth, differentiation, motility, adhesion and tumorigenesis by interaction with the EGF receptor (EGFR), a transmembrane tyrosine kinase growth factor receptor (Boonstra et al, 1995;Mendelsohn and Baselga, 2000;Holbro et al, 2003;Mendelsohn and Baselga, 2003;Shilo, 2003). EGFR, also known as ErbB-1, is the prototype of the ErbB family, which also includes ErbB-2 (c-neu, HER2), ErbB-3 and ErbB-4 (Lin et al, 1984;Bargmann et al, 1986;Kraus et al, 1989;Plowman et al, 1993).…”

“…By heterodimerizing with ErbB members, ErbB-2 augments EGF/EGF-like ligand signaling (Karunagaran et al, 1996;Graus-Porta et al, 1997). EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers (Berger et al, 1988;Xie et al, 1997;Biscardi et al, 2000;Mendelsohn and Baselga, 2000;Stern, 2000;Mendelsohn and Baselga, 2003). Increased expression and signaling of EGFR and/or ErbB-2 is associated with more aggressive clinical behavior and correlates with a poor prognosis (Alroy and Yarden, 1997).…”