EGFR/HER-targeted therapeutics in ovarian cancer

Abstract

Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings.

Figure 1. Design of HER-directed therapeutics

HER family members consist of an extracellular domain (divided into subdomains I–IV, with subdomains I and III regulating ligand binding), a transmembrane domain and an intracellular domain containing an ATP-binding tyrosine kinase domain. Ligand binding induces HER dimerization and transphosphorylation of intracellular domains, initiating signal cascades. Therapeutic antibodies, directed against HER extracellular domains, inhibit ligand binding and/or receptor dimerization, deliver toxic conjugates, and/or recruit immune cells. Small-molecule HER inhibitors reversibly or irreversibly inhibit HER tyrosine kinase activity. Each therapeutic antibody or small-molecule inhibitor shown has been tested in vitro, in vivo or in clinical studies of epithelial ovarian cancer. Cartoon structures of HER family members are not drawn to scale and not based on reported crystal structures.