Pramanik, Arindam, Booth, Andrew, Kobza, Dagmara, Brackenbury, William J, Connell, Simon D, Beales, Paul A and Hughes, Thomas ORCID: https://orcid.org/0000-0003-1169-3386 (2026) EGFR-targeted and MMP-activated membranolytic peptides kill cancer cells specifically in vitro and reduce tumour growth in vivo. Molecular Pharmaceutics. (In Press)

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Abstract

Membranolytic peptides are potential cancer therapeutics, although targeting cancer cells specifically remains an unmet challenge. We have modified the membranolytic peptide MP1, from Polybia paulista, to direct its action specifically to some cancer cells, thereby improving its cancer therapeutic characteristics and reducing its non-specific toxicity. MP1 was modified by addition of sequences allowing binding to the cancer biomarker EGFR, with or without sequences directing cleavage by the cancer biomarker MMP-2. Toxicity was assessed in human breast cell lines and was correlated with EGFR expression and MMP-2 activity. Efficacy as an anti-tumour agent was assessed in MDA-MB-468 xenograft models. C-terminal addition of targeting sequences generally reduced cellular toxicities of peptides relative to wildtype MP1. Cell lines that retained the highest sensitivities to these fusion peptides expressed the highest EGFR and/or MMP-2 levels, supporting specific cytotoxic activity directed to these biomarkers. Treatment with an MMP-2 inhibitor significantly reduced the cell-killing activity of peptides containing MMP-2 cleavage sites, further supporting specific targeting. Fusion peptides significantly induced apoptosis and reduced survival in EGFR/MMP-2 high cancer cells, while sparing EGFR/MMP-2 low cells in standard tissue culture and 3D-spheroids. Systemic treatment with the EGFR-MMP-MP1 fusion significantly reduced tumour size in MDA-MB-468 xenograft models, confirming in vivo efficacy against cancer cells and acceptable systemic toxicity. We conclude that EGFR-MMP-MP1 peptides represent a novel cancer therapeutic for further development.

Item Type:	Article
Status:	In Press
Subjects:	Q Science > Q Science (General)
School/Department:	School of Science, Technology and Health
URI:	https://ray.yorksj.ac.uk/id/eprint/14441

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