Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers

Abstract

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Keywords: HER 2 low; HER2; HER2 discovery; HER2 landmark trials; HER2 role in cancers; HER2DX; anti-HER therapies; biomarker; predictive; prognostic.

Figure 1

Downstream signaling pathway of the HER2 receptor.

Figure 2

HER2 testing using IHC technique in breast cancer. Adapted from ASCO and CAP guidelines [21].

Figure 3

Single-probe ISH testing for evaluation of HER2 gene amplification in breast cancer. Adapted from ASCO and CAP guidelines [21]. (For groups, see Figure 4).

Figure 4

Dual-probe ISH testing for evaluation of HER2 gene amplification in invasive component of breast cancer specimen. Adapted and modified from ASCO and CAP guidelines [21]. CEP—Chromosome enumeration probe-targeting centromere in chromosome 17.