Natural Products Targeting the EGFR/HER2 Axis in Tumorigenesis: Interpretation of Molecular Mechanisms and Recent Insights Into Synergistic Strategies for Cancer Therapy

ABSTRACT The epidermal growth factor receptor (EGFR/HER1) and human epidermal growth factor receptor 2 (HER2) are key members of the ErbB tyrosine kinase receptor family, playing central roles in the pathogenesis of various cancers, including breast, lung, colorectal, and gastric tumors. Their overexpression and activation drive tumor progression, metastasis, and resistance to therapies. Although several EGFR/HER2‐targeted drugs, such as lapatinib, trastuzumab, and afatinib, have been developed, resistance and off‐target toxicities necessitate novel therapeutic strategies. Natural products have emerged as promising candidates for modulating EGFR/HER2 signaling due to their structural diversity, multitarget potential, and favorable safety profiles. This review provides an overview of natural modulators from phenolics, terpenoids, alkaloids, glycosides, saponins, and marine compounds that inhibit EGFR and/or HER2 by blocking phosphorylation, disrupting dimerization, promoting degradation, or modulating downstream pathways such as PI3K/Akt/mTOR, MAPK/ERK, and STAT3. Compounds like curcumin, epigallocatechin gallate (EGCG), resveratrol, quercetin, and berberine demonstrate both direct and synergistic anticancer effects in vitro and in vivo, especially when combined with chemotherapy or radiation. Emphasis is given to dual‐targeting strategies, where natural compounds inhibit both EGFR and HER2, overcoming monotherapy resistance. Molecular docking and in silico simulations further support their binding affinity for ATP‐binding domains of tyrosine kinases. This review also highlights combinatorial approaches using dietary phytochemicals and synthetic inhibitors, paving the way for integrative oncology. In conclusion, natural compounds are valuable bioactive agents with potential to complement EGFR/HER2‐targeted therapies. Future efforts should improve bioavailability, elucidate mechanisms, and validate efficacy through clinical studies.