An MIEN1-based hexamer peptide (LA3IK) inhibits EGF-driven oncogenic signaling in prostate cancer by disrupting EGFR-ERBB2 heterodimerization.

Advanced prostate cancer remains challenging, driven in part by Epidermal Growth Factor (EGF) signaling that promotes migration, invasion, and angiogenesis. We evaluated LA3IK (LAIAVK), a novel MIEN1-based hexapeptide, for its ability to inhibit EGF-mediated tumor progression in androgen-independent, EGFR-overexpressing PC3 prostate cancer cells. Our full assessment included mechanistic studies of receptor dimerization, downstream signaling pathways, and functional assays for cancer cell behaviors. The results show that LA3IK selectively disrupts EGFR–ERBB2 heterodimerization, reducing phosphorylation of EGFR at Y1068 and downstream signaling through NF-κB, Src, and STAT3. This leads to impaired EGF-driven migration and invasion while sparing proliferation. Mechanistically, LA3IK induces a tryptophan blue shift in EGF and inhibits EGFR–ERBB2 interaction. Transcriptomic analyses revealed downregulation of angiogenesis-related genes ANGPTL4 and VEGFC. Crucially, LA3IK exhibited cancer-specificity, inhibiting EGF signaling in prostate tumors while preserving physiological EGFR function in healthy liver tissues. This tissue-specific action underscores LA3IK’s favorable safety profile. We therefore report LA3IK as the shortest peptide to date that effectively inhibits EGF-mediated tumorigenesis in advanced prostate cancer with minimal off-target effects, highlighting its potential as a precise therapeutic agent.