Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

Abstract

Members of the EGFR family of tyrosine kinase receptors are major regulators of cellular proliferation, differentiation, and survival. In humans, abnormal activation of EGFR is associated with the development and progression of many cancer types, which makes it an attractive target for molecular-guided therapy. Two classes of EGFR-targeted cancer therapeutics include monoclonal antibodies (mAbs), which bind to the extracellular domain of EGFR, and tyrosine kinase inhibitors (TKIs), which mostly target the intracellular part of EGFR and inhibit its activity in molecular signaling. While EGFR-specific mAbs and three generations of TKIs have demonstrated clinical efficacy in various settings, molecular evolution of tumors leads to apparent and sometimes inevitable resistance to current therapeutics, which highlights the need for deeper research in this field. Here, we tried to provide a comprehensive and systematic overview of the rationale, molecular mechanisms, and clinical significance of the current EGFR-targeting drugs, highlighting potential candidate molecules in development. We summarized the underlying mechanisms of resistance and available personalized predictive approaches that may lead to improved efficacy of EGFR-targeted therapies. We also discuss recent developments and the use of specific therapeutic strategies, such as multi-targeting agents and combination therapies, for overcoming cancer resistance to EGFR-specific drugs.

Keywords: EGFR mutations; EGFR-targeting drugs; HER-targeted drugs; epidermal growth factor receptor (EGFR); secondary resistance.

Figure 1

Intracellular signaling involving EGFR. The major regulatory pathways downstream of EGFR and other HER receptors are shown. Binding of specific ligands (e.g., EGF) leads to homo- or heterodimerization of receptors, thus resulting in conformational changes in the intracellular kinase domain, which results in phosphorylation and activation of the receptor. The signaling axes RAS-RAF-MEK-ERK and PI3K-AKT-mTOR, in turn, activate various downstream signaling pathways, thus leading to enhanced cell proliferation and survival. Created with BioRender.com (accessed on 1 November 2023).

Figure 2

(a) Ligands that bind to common types of homo- and heterodimers formed by HER receptors. The following designations were used: 1—EGFR, 2—HER2, 3—HER3, and 4—HER4. (b) Dimerization, activation, and internalization of the EGFR receptor. Created with BioRender.com (accessed on 18 October 2023).

Figure 3

(a) Structure of EGFR gene. EGFR exons 18–21 encode the tyrosine kinase domain and may contain mutations, playing a crucial role in the development and progression of different cancers with a strong proven relationship to resistance (red) and sensitivity (green) to specific TKIs. (b) Domain view of EGFR protein. Left, a schematic diagram of ligand-bound dimerized EGFR. Right, sites of inhibition of EGFR activity by different targeted drugs (mAb: monoclonal antibodies; TKIs: tyrosine kinase inhibitors). Created with BioRender.com (accessed on 18 October 2023).

Figure 4

Molecular structures of members of the first and second generations of low molecular mass EGFR tyrosine kinase inhibitors.

Figure 5

Molecular structures of members of the third-generation family of low molecular mass EGFR tyrosine kinase inhibitors.

Figure 6

Structures of candidate molecules for the fourth-generation family of low molecular mass EGFR tyrosine kinase inhibitors.