EGFR-targeted and MMP-activated membranolytic peptides derived from Polybia paulista MP1 kill cancer cells specifically in vitro and reduce tumour growth in vivo
Membranolytic peptides have demonstrated potential as cancer therapeutics, although targeting to cancer cells and reducing toxicity associated with activity in normal cells remain unmet challenges. We have investigated the membranolytic peptide MP1, from Polybia paulista, in order to assess ways to reduce its non-specific toxicity and thereby improve its characteristics as a cancer therapeutic. Using a panel of human breast cell lines and cell survival assays, we show that C-terminal addition of an EGFR binding sequence, with or without a linking MMP-2 cleavage sequence, generally reduced the efficacy of the peptides relative to wildtype MP1, as determined by increases in IC50 values. Critically, cell lines that show the highest sensitivities to these fusion peptides (MDA-MB-468, MDA-MB-231) expressed the highest EGFR and/or MMP-2 levels, demonstrating that these additions direct the cytotoxic activity to cells expressing these biomarkers. MMP-2 inhibition significantly reduced the cell-killing activity of peptides containing MMP-2 cleavage sites, further demonstrating targeting to this biomarker. Fusion peptides significantly induced apoptosis and reduced survival in EGFR/MMP-2 high cancer cells, while sparing EGFR/MMP-2 low cells in the context of standard tissue culture and 3D-spheroids. Finally, systemic treatment with the EGFR and MMP-2 cleavage fusion significantly reduced tumour size in MDA-MB-468 xenograft models, confirming in vivo efficacy against cancer cells and acceptable systemic toxicity. We present this EGFR-MMP-MP1 peptide as a novel cancer therapeutic for further pre-clinical and clinical development.