Targeting the Epidermal Growth Factor Receptor in Epithelial Ovarian Cancer: Current Knowledge and Future Challenges

Abstract

The epidermal growth factor receptor is overexpressed in up to 60% of ovarian epithelial malignancies. EGFR regulates complex cellular events due to the large number of ligands, dimerization partners, and diverse signaling pathways engaged. In ovarian cancer, EGFR activation is associated with increased malignant tumor phenotype and poorer patient outcome. However, unlike some other EGFR-positive solid tumors, treatment of ovarian tumors with anti-EGFR agents has induced minimal response. While the amount of information regarding EGFR-mediated signaling is considerable, current data provides little insight for the lack of efficacy of anti-EGFR agents in ovarian cancer. More comprehensive, systematic, and well-defined approaches are needed to dissect the roles that EGFR plays in the complex signaling processes in ovarian cancer as well as to identify biomarkers that can accurately predict sensitivity toward EGFR-targeted therapeutic agents. This new knowledge could facilitate the development of rational combinatorial therapies to sensitize tumor cells toward EGFR-targeted therapies.

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

“…EGFR is considered to be a key therapeutic target in many types of cancer. However, for reasons that are still unclear, treatment of EOC patients with anti-EGFR results in a very poor response and is not correlated to EGFR expression (Siwak et al, 2010). Therefore, there is an urgent need to further understand the relationships between the tumor microenvironment, EGFR activation and disease outcome in ovarian cancer.…”

Proteomic Analysis of Temporally Stimulated Ovarian Cancer Cells for Biomarker Discovery

“…Although we have demonstrated a modest correlation between EGFR and LAMP-1 expression in ovarian cancer tissue cores, it is important to note that increased expression of EGFR is not always predictive of therapeutic responses to receptor-targeted therapies. This has been demonstrated in both ovarian and colorectal cancers (12,52). Clinical trials performed using an EGFR monoclonal antibody for the treatment of receptor-positive cancers did not demonstrate clinical efficacy as a monoclonal antibody therapy, further illustrating the difficulty of predicting antibody responses based on overexpression alone (53).…”

“…Studies illustrate overamplification of the EGFR gene in between 4% and 22% of ovarian cancers, with aberrant protein expression in up to 60% of ovarian malignancies (10 -12). Aberrant EGFR expression has been associated with high tumor grade, increased cancerous cell proliferation, and poorer patient outcomes (12)(13)(14)(15). Gene amplification and the overexpression of other EGFR family members such as Her2 and ErbB3 have also been reported in epithelial ovarian cancers (15).…”

“…Although EGFR inhibitors exhibit modest success in vitro, no agents have been approved by the U.S. Food and Drug Administration for the treatment of malignant ovarian tumors (17). Among other therapeutic approaches, studies have looked at the potential efficacy of the TKIs erlotinib and gefitinib in the treatment of ovarian cancers; unfortunately, neither drug was effective in eliciting a significant response in ovarian tumor treatment (12,15,18,19). However, the identification of markers of pathwaystimulated processes might help to stratify disease and select patients with EGF signaling activation.…”

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

“…TKIs combined with cytotoxic chemotherapy, anti-angiogenic therapy, or hormonal therapy have also shown limited clinical efficacy and in some cases excessive toxicity (Campos et al 2010, Chambers et al 2010, Nimeiri et al 2008, Vasey et al 2008. The reason behind the relative failure of EGFR targeted therapies is not understood, but may be related to constitutive activation of downstream pathways, overexpression of ligands, or activation of alternative signaling pathways (reviewed in (Bianco et al 2007, Siwak et al 2010). Despite the promising preclinical results based on the amplification data, these therapeutic agents cannot be recommended outside of a clinical trial setting for the treatment of ovarian cancer.…”