Oral Presentation The 16th Australian Peptide Conference 2025

Cyclic host-defense peptides kill proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance (129410)

Aurélie Benfield 1 2 , Felicitas Vernen 3 , Reuben Young 4 5 , Ferran Nadal-Bufí 1 , Henry Lamb 1 2 , Heinz Hammerlindl 6 , David Craik 2 3 , Nicole Lawrence 2 3 , Helmut Schaider 6 , Stephen Blanksby 5 7 , Sonia Troeira Henriques 1 2
  1. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute , Brisbane, QLD, Australia
  2. ARC Centre of Excellence for Innovations in Peptide and Protein Science, Brisbane, QLD, Australia
  3. Institute of Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  4. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
  5. Central Analytical Research Facility, School of Chemistry and Physics, Faculty of Science, Queensland University of Technology, Brisbane, QLD, Australia
  6. Frazer Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
  7. School of Chemistry and Physics, Faculty of Science, Brisbane, QLD, Australia

Metastatic melanoma remains a highly lethal cancer, largely due to the rapid emergence of resistance to current therapies. Despite recent advances with targeted therapies and immune checkpoint inhibitors, many patients fail to respond or relapse within months due to acquired drug resistance. To address this challenge, we investigated a novel therapeutic approach using membrane-disruptive cyclic peptides to eliminate melanoma cells that evade conventional treatments. Our study profiled lipidomic and proteomic changes in melanoma cells during the development of resistance to dabrafenib, a BRAF inhibitor used in BRAFV600E-positive melanoma. We then evaluated the efficacy of two cyclic peptides, cyclic tachyplesin I (cTI) and cyclic gomesin (cGm) which exhibit rapid, membrane-targeted cytotoxicity. These peptides effectively eliminated drug-naïve, drug-tolerant, and drug-resistant melanoma cells in vitro, without inducing further resistance even upon prolonged exposure of cTI. Notably, in a mouse model, combination therapy with cTI and dabrafenib reduced metastatic burden and improved overall survival compared to dabrafenib alone. Our findings support the potential of cyclic peptides to be developed both as standalone agents and in combination therapy to overcome resistance and improve outcomes in metastatic melanoma.