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.

Figure 1

Structure of EGFR. EGFR consists of extracellular, transmembrane, and intracellular domains. The extracellular domain is the least conserved domain among the EGFR family members and consists of 4 subdomains—two ligand-binding domains and two receptor dimerization domains, which are cysteine-rich (reviewed in [12]). The transmembrane domain, which spans the cell membrane, is hydrophobic. The cytoplasmic tail of the EGFR family is highly conserved and contains the tyrosine kinase domain. Activation of EGFR family members leads to autophosphorylation of the tyrosine residues in the cytoplasmic tail. The phosphorylated tyrosine residues become docking sites for proteins with SRC homology 2 and phosphotyrosine binding domains, which transduce the signals downstream. EGFR phosphorylation at selected residues and their functional outcomes are indicted in the diagram. T: threonine; Y: tyrosine.

Figure 2

Selected representation of canonical EGFR family signaling pathways. The EGFR family consists of 4 members: EGFR, HER2, HER3, and HER4 (indicated by numbers 1–4 in the diagram). EGFR family ligands include EGF-and EGF-like ligands, transforming growth factor (TGF)-α and heregulins (HRGs, also known as neuregulins, NRGs). As indicated by the numbers in parentheses beneath the ligands, each ligand binds preferentially to a particular EGFR family member. HER2, while lacking any known ligand, is the preferred binding partner of for all EGFR family members. HER3 lacks intrinsic kinase activity due to mutation of critical amino acids in the kinase domain; therefore, it is inactive on its own or as a homodimer. Transduction of EGFR signals occurs through intracellular adaptor proteins, which transmit signals through cascades such as the RAS/RAF/MEK/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3′-kinase (PI3K)/AKT cascades. The downstream proteins in these signaling cascades can shuttle from the cytoplasm to the nucleus, where they signal to transcription factors and their complexes such as MYC, ELK, and FOS/JUN. Signal transduction through the EGFR family to downstream pathways and cascades controls diverse cellular responses such as proliferation, differentiation, cell motility, and survival as well as tumorigenesis. Figure adapted from [13]. Abbreviations: PLCγ: Phospholipase Cγ; SHP2: SRC homology phosphatase 2; GAP: GTPase activating protein; SHC: SRC homology 2 domain and collagen-containing protein; PKC: Protein kinase C; MEK: MAPK/ERK kinase; PAK: P21-activated kinase; JNKK: JNK kinase; JNK: JUN N-terminal kinase; EGR1: Early growth response protein 1; STAT: Signal transducer and activator of transcription.