P6-SN38: A Novel EGFR-Targeting Cyclic Peptide–Drug Conjugate with Potent Activity Against NSCLC"

The epidermal growth factor (EGF) and its receptor (EGFR) play critical roles in cancer progression by regulating cell proliferation, differentiation, and migration, making the EGFR signaling axis a prime target for cancer therapy. Although monoclonal antibodies and small-molecule kinase inhibitors targeting EGFR have been clinically approved, their efficacy is often limited by the rapid emergence of drug resistance.

In this study, we present the design, synthesis, and biological evaluation of a novel EGFR-targeted peptide–drug conjugate (PDC), P6-SN38. This conjugate comprises the EGFR-specific cyclic peptide P6 linked to SN38, the active metabolite of irinotecan and a potent topoisomerase I inhibitor. SN38 is conjugated to P6 via a mono-succinate linker at the tertiary hydroxyl group on the E-ring (position 20), preserving its cytotoxic potential while enabling selective delivery.

P6-SN38 demonstrated potent, sub-micromolar anticancer activity in EGFR-overexpressing (EGFR⁺) cancer cell lines, with no cytotoxicity observed in EGFR-negative (EGFR⁻) cells. In vivo, the conjugate selectively accumulated in EGFR⁺ non-small cell lung cancer (NSCLC) xenografts and significantly outperformed both free SN38 and the anti-EGFR antibody cetuximab (Erbitux™) in tumor inhibition. Notably, treatment with 10 mg/kg of P6-SN38 completely eradicated EGFR⁺ tumors with minimal toxicity, while showing no effect on EGFR⁻ tumors in a side-by-side xenograft model.

These findings support P6-SN38 as a promising targeted therapeutic for EGFR-overexpressing cancers and highlight the potential of cyclic peptide-based conjugates in overcoming limitations of current EGFR-directed therapies.