Poster Presentation 14th Australian Peptide Conference 2022

Hairpin peptides kill metastatic BRAF mutant melanoma cells that have acquired drug-resistance (#109)

Aurelie Benfield 1 , Felicitas Vernen 2 , Reuben Young 3 , Ferran Nadal-Bufi 1 , Heinz Hammerlindl 4 , David Craik 2 , Helmut Schaider 4 , Nicole Lawrence 2 , Stephen Blanksby 3 , Sonia Troeira Henriques 1
  1. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute , Brisbane, QLD, Australia
  2. Institute of Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  3. Central Analytical Research Facility, School of Chemistry and Physics, Faculty of Science, Queensland University of Technology, Brisbane, QLD, Australia
  4. Diamentina Institute, University of Queensland, Translational Research Institute , Brisbane, QLD, Australia

Melanoma is a deadly cancer due to its metastatic nature. In the last decade, the overall survival rate of patients with metastatic melanoma has greatly improved thanks to targeted therapy and immune check points inhibitors. Nevertheless, about half of the patients are irresponsive, or develop drug-resistance within 6-10 months of treatment. We therefore require alternative classes of drugs that have distinct mechanisms of action to treat melanoma patients. We investigated the use of cyclic peptides inspired on host defense peptides from spider and horseshoe crab with a β-hairpin structure as an alternative therapeutic option to kill drug-tolerant and drug-resistant melanoma cells. We explored the activity of these anti-melanoma peptides and characterised the lipidome and proteome of untreated melanoma cells and ones that have acquired drug-resistance to dabrafenib, a small molecule inhibitor used to treat patients with metastatic melanoma with BRAF V600E mutation. We discovered that i) the cell membrane lipid composition of melanoma cells changed while acquiring resistance to dabrafenib, ii) that both peptides could kill metastatic melanoma cells during each stage of developing drug resistance iii) and metastatic melanoma cells did not acquire resistance to tested peptides. These host defense peptides are therefore well suited as templates to design novel therapeutic leads to target drug-resistant metastatic melanoma cells and/or as a co-treatment option with small molecule drugs.