EGFR/SRC-mediated EMT

Overview

EGFR/SRC-mediated epithelial-mesenchymal transition (EMT) refers to a coordinated oncogenic signaling axis in which the Epidermal Growth Factor Receptor (EGFR) and the non-receptor tyrosine kinase SRC act in concert to drive the transcriptional and phenotypic reprogramming that converts epithelial tumor cells into a mesenchymal, invasive state. EMT is a critical process in the metastasis cascade: cells undergoing EMT lose their characteristic polarity and cell–cell adhesion properties, acquire migratory and invasive capabilities, and become resistant to apoptosis and conventional therapies. EGFR, a receptor tyrosine kinase that transduces extracellular growth factor signals into intracellular proliferative and survival responses, and SRC, a cytoplasmic tyrosine kinase that amplifies and diversifies those signals through downstream effectors including PI3K/Akt1 signaling, RAS/MAPK activation, and JAK2/STAT3 signaling pathway, together form a convergent hub that regulates the expression of EMT transcription factors, matrix metalloproteinase-9, and other mediators of extracellular matrix remodeling and tumor invasion. Network pharmacology analyses across multiple recent studies have consistently ranked SRC and EGFR among the highest-degree hub proteins in cancer-associated protein interaction networks, underscoring the centrality of this dual axis in tumor biology.

The biological significance of the EGFR/SRC-mediated EMT axis extends across a broad range of malignancies, including oral, colorectal, liver cancer, breast, head/neck, bladder cancer, ovarian cancer, and prostate tumors, as well as lung and gastric cancers. The axis is further potentiated by cancer-associated fibroblast-derived signals—including growth factors TGF-β1 and VEGF and FGF2-PI3K-Akt1 signaling—and by tumor microenvironmental cues such as hypoxia, nuclear factor kappa B activation, and MYC amplification. Consequently, therapeutic targeting of EGFR and SRC, individually or in combination, has emerged as a strategy to simultaneously suppress tumor proliferation, metastasis, and treatment resistance.

Focus of Latest Publications

Recent publications have continued to examine EGFR/SRC-mediated EMT as a mechanistic node in cancer progression and therapeutic response, particularly in studies of anti-metastatic and pathway-targeted interventions. In oral cancer cells, imipramine was reported to target apoptosis, metastasis, and EGFR/SRC-mediated EMT, indicating that this signaling axis was investigated in the context of suppressing malignant progression. In glioma, scutellarein was found to inhibit proliferation, invasion, and migration while inducing apoptosis and oxidative stress; network pharmacology and transcriptomic analyses suggested SRC and EGFR among its potential targets, with effects verified through modulation of the PI3K/Akt signaling pathway. These findings place EGFR/SRC-linked EMT within broader oncogenic signaling networks that also include PI3K/AKT-driven survival and motility programs.

Other recent studies connected EGFR/SRC-related signaling to resistance phenotypes and tumor microenvironment remodeling. In castration-resistant prostate cancer, dual targeting of DNMTs and EZH2 reactivated ADAMTS1, promoted collagen degradation, suppressed FAK/MAPK mechanotransduction, and reversed epithelial-mesenchymal transition, thereby overcoming stromal-mediated resistance and immunosuppression. Although EGFR/SRC-mediated EMT was not the sole focus, this work reinforces the importance of EMT-associated signaling in therapy resistance and niche adaptation. In hepatocellular carcinoma, bile acid accumulation was shown to activate EGFR signaling and drive tyrosine kinase inhibitor resistance, further underscoring the relevance of EGFR-centered pathways in resistant disease states that may intersect with EMT programs.

Several natural products and multi-component formulations were also studied through network pharmacology approaches that implicated EGFR and SRC as candidate targets relevant to EMT-associated malignancy. Yinxingye tablets were predicted to act through hub targets including SRC and, in some analyses, EGFR-linked signaling. Jacobaea maritima extract was similarly suggested to target EGFR in pancreatic cancer cells, while sanguinarine metabolite networks centered on SRC and PIK3CA. In ischemic stroke and diabetic kidney disease models, SRC and EGFR appeared among predicted targets in broader signaling analyses, reflecting the frequent co-occurrence of these proteins in pathway mapping even outside cancer. Collectively, the recent literature supports EGFR/SRC-mediated EMT as a recurring mechanistic theme in studies of invasion, metastasis, resistance, and pathway crosstalk, with experimental and computational work converging on EGFR- and SRC-associated signaling as actionable nodes.