Epidermal growth factor receptor (EGFR), also referred to as ERBB1 or HER1 is part of a broader ERBB family of receptor tyrosine kinases and plays a crucial role in the regulation of cell growth, survival, proliferation, and differentiation. EGFR is activated by several mechanisms including binding to specific ligands, such as the epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) as well as by overexpression or mutation. This activation then triggers a cascade of downstream signaling pathways, including the MAPK, PI3K/Akt, and JAK/STAT pathways, which are involved in various cellular processes. The critical role of EGFR in some of these cell signaling pathways therefore makes it a primary target in cancer therapy.
Many cancers, including non-small cell lung cancer (NSCLC), colorectal, head and neck squamous cell carcinoma, and glioblastoma exhibit overexpression of EGFR. Overexpression often leads to increased receptor activity and promotes uncontrolled cell division and tumor growth. Today, a large number of EGFR inhibitors have been developed for cancer treatment, including: Monoclonal Antibodies (e.g. cetuximab, panitumumab) that target the extracellular domain of EGFR, preventing ligand binding and receptor dimerization; Tyrosine Kinase Inhibitors (TKIs): (e.g. osimertinib, gefitinib, erlotinib, and afatinib) that inhibit the kinase activity of EGFR by binding to its ATP-binding site, these are particularly effective in cancers with specific EGFR mutations; and Antibody-Drug Conjugates (ADCs): These are complex molecules that link a monoclonal antibody specific to EGFR to a cytotoxic drug, allowing targeted delivery of chemotherapy to cancer cells expressing EGFR. These therapies aim to inhibit EGFR signaling and subsequently control cancer growth. However, these agents have shown efficacy only in a few types of cancers and resistance due to secondary mutations in the EGFR gene or activation of alternative signaling pathways to these inhibitors remains a significant challenge in cancer treatment.
Specific mutations in the EGFR gene can lead to constitutive activation of the receptor, independent of ligand binding and testing for EGFR mutations is important in the management of certain cancers to determine the suitability of targeted therapies. Common mutations include deletions in exon 19 and point mutations in exon 21 (e.g., L858R). These mutations are particularly prevalent in NSCLC and are associated with sensitivity to certain targeted therapies. Other important examples of oncogenic drivers of NSCLC are mutations in exons 18-21, frequently identified (10-60% of lung adenocarcinomas) among patients successfully treated with first-generation TKIs and in-frame insertions of three or more base pairs in exon 20 (Ex20Ins), unresponsive to TKIs and accounting for 4-10% of all EGFR mutations in NSCLC. Additionally, well described mutations in the EGFR gene, such as T790M also in NSCLC, can reduce the binding affinity of first and second generation TKIs.
At NeoGenomics Laboratories, Inc. we offer a wide range of assays and modalities that can address specific mutations and status of EGFR from clinical samples. The use of our molecular profiling assays with PCR/ddPCR, next-generation sequencing (NGS) or even Sanger sequencing technology enables the precise identification and characterization to detect the highly recurrent EGFR alterations in exon 18-21.
Additional sources of resistance have also been attributed to the intratumoral heterogeneity of gene mutations, gene expression or interactions between tumor cells, and stroma in the tumor microenvironment (TME). Therefore, an understanding of EGFR status within the context of the TME and its spatial distribution can provide insights into cancer progression and potential new therapeutic strategies. This highly dynamic TME consists of various cell types, including cancer cells, stromal cells, immune cells, and endothelial cells, embedded within the extracellular matrix (ECM) and consists of several key components including:
- Cancer-Associated Fibroblasts (CAFs): These cells support tumor growth and metastasis by remodeling the ECM and secreting growth factors, including EGF.
- Immune Cells: Tumor-associated macrophages (TAMs), T cells, and other immune cells can either support or inhibit tumor growth, depending on their activation state.
- Endothelial Cells: These cells form the blood vessels that supply the tumor with nutrients and oxygen, facilitating tumor growth and metastasis.
The spatial distribution of EGFR within the tumor and its microenvironment is therefore critical for understanding how signals are propagated and how different cells within the TME interact. EGFR signaling can also contribute to the modification of the TME, promoting angiogenesis (the formation of new blood vessels) which is crucial for tumor growth and metastasis. At NeoGenomics Laboratories, Inc. we offer a wide array of advanced imaging techniques, such as immunohistochemistry (allowing for the visualization of EGFR expression in tissue sections, providing information on the localization of EGFR-positive cells), fluorescence in situ hybridization (FISH, which can detect EGFR gene amplification and mutations at a single-cell level within the spatial context of the tissue) and spatial multiplexed Immunofluorescence and spatial transcriptomics (the mapping of EGFR specific expression profiles to their spatial locations within the tissue providing a comprehensive view of the molecular landscape of the TME).
In conclusion, EGFR is a critical driver of oncogenesis in several cancers due to its role in regulating key cellular processes. Targeting EGFR has proven to be an effective strategy in treating certain types of cancer, although resistance remains a significant challenge. Understanding the mechanisms of EGFR signaling and resistance continues to be an area of active research, with the goal of improving therapeutic outcomes for cancer patients.