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

Cancer research · Prostate cancer · EGFR · ERBB2

LA3IK selectively disrupts EGFR–ERBB2 heterodimerization, reducing phosphorylation of EGFR at Y1068 and downstream signaling through NF‑κB, Src, and STAT3, thereby impairing EGF‑driven migration and invasion while sparing proliferation.

Advanced prostate cancer remains challenging, driven in part by 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. 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. LA3IK exhibited cancer‑specificity, inhibiting EGF signaling in prostate tumors while preserving physiological EGFR function in healthy liver tissues, underscoring its favorable safety profile. LA3IK represents the shortest peptide to date that effectively inhibits EGF‑mediated tumorigenesis in advanced prostate cancer with minimal off‑target effects.

The study identifies a small, selectively acting peptide that interrupts malignant EGFR signaling in prostate cancer without affecting normal EGFR functions, potentially offering a safer therapeutic option with reduced toxicity compared to broad‑spectrum EGFR inhibitors.

Evidence level: Számítógépes vagy elméleti. Modellből vagy adatbányászatból származó jel.

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