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Epidermal growth factor receptor (EGFR) is an important target on cancer therapy. One of the approaches is to modulate EGFR induced ligand-binding affinity change. In order to understand the correlation between ligand-binding change and EGFR modulation, we try to get some small molecular agents from traditional Chinese medicines (TCMs) to modulate EGFR activity on the biosensor system. Among 60 of TCMs, we find that some samples exhibit different influence on EGFR modulation. Among these, 051 showed a more inhibitive property due to decreasing EGF-affinity, -binding to EGFR and existed an anti-EGFR activity to A549 cells. On the other hand, 040 exist opposite function to 051. 040 is a most powerful enhancer that can increase the affinity and quantity of EGF binding to EGFR and a pro-EGFR activity on cell culture system. In our study, we can successfully regulate the EGFR-mediated cell proliferation and anti-apoptosis by modulating the affinity of EGF-EGFR interaction. This way will be a useful method to apply on the therapy of human diseases.