Abstract
Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.
Highlights
The expression of the erythroblastic leukemia viral oncogene homolog (ERBB) family is closely linked to tumor progression through the constitutive activation of downstream signaling, such as the epidermal growth factor (EGF) receptor (EGFR) pathway or through a somatic mutation; ERBB expression is enhanced during tumor microenvironment (TME)
The therapeutic efficacy of panitumumab alone and in combination with FOLFOX4 chemotherapy that includes oxaliplatin, fluorouracil (FU), and leucovorin in patients with advanced CRC (aCRC) with RAS mutations was poorer than that in patients with wild-type RAS [100]. These results suggest that patients with colorectal cancer (CRC) with elevated epidermal growth factor receptor (EGFR) signaling would be more sensitive to the anti-EGFR therapy
Drug resistance caused by oncogene mutations or activation of oncogenic signaling pathways and increased tumor plasticity is the major obstacle encountered in the application of target therapies such as anti-EGFR therapy [91,127]
Summary
The expression of the erythroblastic leukemia viral oncogene homolog (ERBB) family is closely linked to tumor progression through the constitutive activation of downstream signaling, such as the epidermal growth factor (EGF) receptor (EGFR) pathway or through a somatic mutation; ERBB expression is enhanced during tumor microenvironment (TME). The transmembrane EGFR ligands comprise an N-terminal signal peptide, pro-peptide region, the EGF-lik short juxtamembrane stalk, a hydrophobic transmembrane domain, and a cytoplasmic domain (Figure 1A). Ligands such as BTC, HB-EGF, EREG, and NRG1-4 interact with the ERBB4. ERBB2 proteins can be activated through interaction with other ERBBs. G-protein-coupled receptors (GPCRs) stimulate specific metalloproteinases, such as disintegrin and metalloproteinase (ADAM) family members, resulting in EGFR pro-ligand cleavage and transactive EGFR downstream cascade [13] (Figure 1E). The efficacy and specificity of intracellular signaling pathways are regulated by specific ligands, receptor dimerization, and interacting proteins that bind to the phosphorylated domains of ERBB [17]. The efficacy and specificity of intracellular signaling pathways are regulated by specific ligands, receptor dimerization, and interacting proteins that bind to the phos of 27 phorylated domains of ERBB [17].
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