Human epidermal growth factor receptor family-targeted therapies in the treatment of HER2-overexpressing breast cancer

Abstract

Breast cancer characterized by overexpression of human epidermal growth factor receptor 2 (HER2) has been associated with more aggressive disease progression and a poorer prognosis. Although an improved understanding of breast cancer pathogenesis and the role of HER2 signaling has resulted in significant survival improvements in the past 20 years, resistance to HER2-targeted therapy remains a concern. A number of strategies to prevent or overcome resistance to HER2-targeted therapy in breast cancer are being evaluated. This article provides a comprehensive review of (a) the role of HER2 signaling in breast cancer pathogenesis, (b) potential receptor and downstream therapeutic targets in breast cancer to overcome resistance to HER2-targeted therapy, and (c) clinical trials evaluating agents targeting one or more members of the HER family and/or downstream pathways for the treatment of breast cancer, with a focus on metastatic disease.

Keywords: Breast cancer; Epidermal growth factor receptor; Human epidermal growth factor receptor tyrosine kinase receptor family; Tyrosine kinase inhibitor.

Figure 1.

Downstream effectors of HER signaling. Figure adapted from Atalay et al. [77] by permission of Oxford University Press. Abbreviations: Akt, protein kinase B; EGFR, epidermal growth factor receptor; Gab 1, GRB2-associated binding protein 1; GDP, guanosine 5′-diphosphate; Grb2, growth factor receptor-bound protein 2; GTP, guanosine-5′-triphosphate; HER, human epidermal growth factor receptor; HSP90, heat shock protein 90kDa α; IGF-1R, insulin-like growth factor-1 receptor; JNK, mitogen-activated protein kinase 8; MAPK, mitogen-activated protein kinase 1; MEK1, mitogen-activated protein kinase kinase 1; MEKK, mitogen-activated protein kinase kinase kinase 1; mTOR, mechanistic target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PLCγ, phospholipase C γ; PTEN, phosphatase and tensin homolog; Rac, v-akt murine thymoma viral oncogene homolog 1; Raf1, v-raf-1 murine leukemia viral oncogene homolog 1; Ras, Ras kinase family; Rho, rhodopsin; SEK, simple epithelial keratin; Shc, SHC (Src homology 2 domain containing) transforming protein 1; SOS, son of sevenless homolog; Src, sarcoma virus oncogene.