A Comprehensive Review of HER2 in Cancer Biology and Therapeutics

Abstract

Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly in breast and gastric cancers, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. HER2-activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, and diagnostic approaches, as well as therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes.

Keywords: ADC; HER2; cancer; immune regulation; metastasis; therapeutics.

Figure 1

Schematic representation of HER2 signaling regulation. HER2 is the preferred partner for forming heterodimers (pairing) with other EGFR family members, such as HER1 (EGFR), HER3, and HER4. When a ligand binds to other EGFR family members, dimerization occurs, which activate the intrinsic tyrosine kinase activity of HER2, resulting in initiating downstream signaling cascades. These pathways contribute to regulating gene expression, cell cycle progression, cell motility, and other cellular functions. Figure was made using BioRender.

Figure 2

Dysregulation of HER2. The expression of HER2 is primarily regulated at the level of gene transcription. Transcription factors and epigenetic modifications can regulate HER2 gene expression by modulating the chromatin structure and accessibility to transcriptional machinery. Endocytosed receptors can undergo lysosomal degradation, leading to the attenuation of HER2-mediated signaling pathways. Figure was made using BioRender.

Figure 3

Evolution of HER2-based drugs and mechanisms. The timeline at the top shows when the corresponding HER2-based drugs were approved by the FDA. The corresponding mechanisms are at the bottom. Figure made using Biorender.