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.

Key Publications

• NEWJun Survival outcomes and a prognostic nomogram in EGFR-mutant non-small cell lung cancer with leptomeningeal metastasis: a real-world cohort study. (Journal of neuro-oncology, 2026, PMID 42360664): "Leptomeningeal metastasis (LM) carries a poor prognosis in EGFR-mutant non-small cell lung cancer (NSCLC)."
• NEWJun Targeting the DNA methylation-H3K27me3 switch reverses castration resistance and immunosuppression via ADAMTS1-driven collagenolysis. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42313934): "...suppress FAK/MAPK mechanotransduction signaling, and reverse epithelial-mesenchymal transition (EMT)."
• Jun Integrated UPLC-QTOF-MS and Network Pharmacology for Predicting Active Constituents and Pharmacological Mechanisms of Yinxingye Tablets Against Oxidative Stress. (Biomedical chromatography : BMC, 2026, PMID 42104588): "Based on virtual target prediction, 211 targets of 76 active constituents with identifiable structures were identified, and HSP90AA1, SRC, CASP3, MAPK8, MMP9, IGF1, RAF1, and PPARG were defined as the hub targets involved in the antioxidant stress effects of Yinxingye tablets."
• May Imipramine Targets Apoptosis, Metastasis, and EGFR/SRC-mediated EMT in Oral Cancer Cells. (Anticancer research, 2026, PMID 42049326): "Imipramine Targets Apoptosis, Metastasis, and EGFR/SRC-mediated EMT in Oral Cancer Cells."
• May SPECT/NIR Fluorescence Bimodal Use of Aza-BODIPY Probe Coupled with Cetuximab for Detection of Cancer: Proof of Concept on a Preclinical Head and Neck Squamous Cell Carcinoma Model. (Journal of medicinal chemistry, 2026, PMID 42012405): "The resulting probe efficiently targets EGFR-expressing tumors in a murine model of head and neck squamous cell carcinoma (HSNCC)."
• Apr Scutellarein inhibits the malignancy of gliomas by modulating the PI3K/AKT signaling pathway. (Biochemical and biophysical research communications, 2026, PMID 41966746): "Network pharmacology and transcriptomic analyses suggested that scutellarein may target SRC, EGFR, and AKT1; and exerts its effects through the PI3K/AKT signaling pathway, which was subsequently verified by further experiments."
• Mar Potentiating BSEP-mediated bile acid efflux reverses first-line tyrosine kinase inhibitor resistance in hepatocellular carcinoma. (Cancer letters, 2026, PMID 41903671): "BSEP expression deficiency leads to intracellular accumulation of primary conjugated bile acids (BAs)-especially glycocholic acid (GCA)-which activates EGFR signaling and drives resistance;"
• May Apoptotic/cell cycle arrest potential of dusty miller methanol extract against Paca-2 pancreatic cancer cells via upregulating Bax/Bcl2: A HPLC-ESI-MS/MS, GNPS-based molecular networking and network pharmacology studies. (Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2026, PMID 41895184): "Network pharmacology predicted that JM-derived phenolics target pancreatic cancer-related proteins, notably EGFR and STAT3, suggesting a multi-compound and multi-target mechanism."
• Jun Integrated systems pharmacology-based exploration of sanguinarine: Comprehensive metabolite identification, enzyme mapping, and network analysis. (Bioorganic chemistry, 2026, PMID 41844053): "the major metabolites collectively target a protein network centered on hubs such as PIK3CA and SRC."
• Mar Sanhuang xiexin decoction ameliorates gastric ulcers by activating EGFR/PI3K/AKT pathway based on "drug-target-metabolite" network. (Journal of ethnopharmacology, 2026, PMID 41831741): "Sanhuang xiexin decoction ameliorates gastric ulcers by activating EGFR/PI3K/AKT pathway based on 'drug-target-metabolite' network."