The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer

Abstract

The epithelial growth factor receptor (EGFR) family of receptor tyrosine kinases has been reported to have an active role in a number of malignancies. Amplifications and overexpression of various EGFR family members, including EGFR, Her2, and ErbB3, have been reported in epithelial ovarian cancer. Although anti-EGFR-targeted therapy has shown limited clinical activity in ovarian cancer to date, a recent report suggests that activation of ErbB3, one of the members of the EGFR family, may support the growth and proliferation of ovarian cancer cells and that ErbB3 may therefore serve as a potential therapeutic target in this disease. Here, we review the EGFR family and the clinical experience with anti-EGFR family member-directed therapies in ovarian cancer to date.

Increased DNA methyltransferase activity and DNA methylation following epidermal growth factor stimulation in ovarian cancer cells

“…Epigenetic drugs such as AZA, as well as EGFR targeted drugs, have received some attention in treating platinum-resistant ovarian cancer. [45][46][47] Ovarian cancer progression is positively correlated reflect a more advanced tumor stage. Data obtained from A1 cells closely resembled data obtained for cells treated with EGF longterm.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…Further studies will be necessary to determine whether lapatinib may be a useful agent in ovarian cancer. The roles of HER3 and HER4 in ovarian cancer have been less extensively studied (Sheng and Liu 2011). HER3 amplification and overexpression in ovarian cancer has been described and in one study was significantly associated with poor survival (median survival time 3.3 years vs. 1.8 years for patients with low vs. high HER3 expression) (Sheng and Liu 2011, Tanner et al 2006, Tsuda et al 2004.…”

“…Antibodies directed against the extracellular domain of HER3 diminished HER2 activity and attenuated the activation of downstream effectors (van der Horst et al 2005). Compensatory overexpression of HER3 has also been implicated as a mechanism of resistance to other EGFR inhibitors (Sheng and Liu 2011). These data suggest that targeting HER3 may be an effective treatment strategy and three monoclonal antibodies that target HER3 are being tested in early phase clinical trials for advanced solid tumors (U3-1287, MM-121, and MM-111 which targets both HER2 and HER3).…”

“…The roles of HER3 and HER4 in ovarian cancer have been less extensively studied (Sheng and Liu 2011). HER3 amplification and overexpression in ovarian cancer has been described and in one study was significantly associated with poor survival (median survival time 3.3 years vs. 1.8 years for patients with low vs. high HER3 expression) (Sheng and Liu 2011, Tanner et al 2006, Tsuda et al 2004. Antibodies directed against the extracellular domain of HER3 diminished HER2 activity and attenuated the activation of downstream effectors (van der Horst et al 2005).…”

“…Activated dimers recruit signaling molecules through a phosphorylated cytoplasmic domain that initiates a signaling cascade leading to the activation of downstream pathways such as PI3K-AKT and MAPK that ultimately regulate cellular proliferation, migration, invasion, and apoptosis. Two recent excellent reviews have been published on the role of these receptors in ovarian cancer (Sheng andLiu 2011, Siwak et al 2010); herein we will focus on the clinical implications of EGFR, HER2/neu and HER3, the three receptors found to be amplified in ovarian cancers. Amplification of the EGFR gene has been identified in 4-22% of ovarian cancers and, for the most part, amplification correlates with overexpression (Dimova et al 2006, Lassus et al 2006, Stadlmann et al 2006, Vermeij et al 2008.…”