Resisting resistance

According to the Australian Cancer Council Federation, at least 2 in 3 Australians will be diagnosed with a type of skin cancer in their lifetime, with a higher risk for men to develop non-melanoma and melanoma skin cancers, compared to women. It was also reported that over 60% of mortality from skin cancer in Australia occur in men. Melanoma is the deadliest and most hostile form of skin cancer, and current effectiveness of small molecular drug treatments are weakening due to the increased likelihood of the cancer cells developing drug-tolerance and resistance to the therapy with continued exposure of the drug.  

 Membrane-active peptides offer an alternative strategy to develop therapies to kill drug-tolerant cells and avoid resistance in melanoma cells. Cyclic membrane-active peptides can do this by avoiding known drug-resistant mechanisms and targeting ‘non-proliferative cells’ that are the primary culprit to cancer cells developing drug-tolerance and resistance. Non-proliferative cells are dormant cells that do not actively divide; hence they are also known as slow-cycling cells. A team of researchers in CIPPS, including Chief Investigators Professor David Craik and Associate Professor Sónia Troeira Henriques, Associate Investigator Professor Stephen Blanksby, Research Fellows Dr Aurelie Benfield and Dr Nicole Lawrence, PhD student Henry Lamb, and CIPPS alumni Dr Ferran Nadal-Bufi, have investigated the effectiveness of cyclic peptides inspired by host-defense peptides derived from horseshoe crabs and tarantula spiders. 

Our CIPPS researchers successfully identified the cyclic tachyplesin I, from the horseshoe crab, as an ideal candidate in the destruction of non-proliferative melanoma cells. The peptide did not trigger drug-tolerance and resistance in these cancer cells after prolonged exposure. Further experimentation using mice with grafted melanoma cells showed that they were more likely to survive and have fewer metastases after treatment with cyclic tachyplesin I and dabrafenib (a known small molecular drug for treating melanoma), than treatment with dabrafenib alone. Our CIPPS researchers were the first to demonstrate the effectiveness of using cyclic membrane-active peptides in alleviating melanoma drug-tolerance and resistance. This research paves the way for the development of new anticancer therapeutics that act via a novel mechanism of action. 

Citation: Benfield, A. H., Vernen, F. Young, R.S., Nadal-Bufi, F., Lamb, H. et al. Cyclic tachyplesin I kills proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance 2024 Pharmacol. Res. 107298. 

Doi: 10.1016/j.phrs.2024.107298 

CIPPS contributors: Sónia Troeira-Henriques, David Craik, Stephen Blanksby, Aurelie Benfield, Felicitas Vernen, Reuben Young, Ferran Nadal-Bufi, Henry Lamb, Heinz Hammerlindl, Helmut Schaider, Nicole Lawrence.