Oral Presentation Australasian Society for Dermatology Research 2022 Annual Scientific Meeting

Phenotypic characterisation of early melanoma persisters in adaptive cancer drug resistance (#110)

Joachim Torrano 1 , Heinz Hammerlindl 1 2 , Sabrina Hammerlindl 1 2 , Dinoop Ravindran-Menon 1 3 , Abdullah A Emran 1 4 , Natalie Bordag 5 , Elmar Zuegner 5 , Nikolas K Haass 6 , Martin Sadowski 7 , Jennifer Stow 8 , Christoph Magnes 5 , Helmut Schaider 1
  1. Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
  2. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
  3. Department of Dermatology, School of Medicine, University of Colorado, Aurora, CO, USA
  4. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
  5. Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria
  6. Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
  7. Australian Prostate Cancer Research Centre, Brisbane, QLD, Australia
  8. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

While advances made over the last decade in immune checkpoint inhibitors and molecular targeted therapies significantly improved survival for patients with advanced melanoma, a large proportion of patients still do not respond effectively to treatment and many patients experience disease relapse. Cancer cells that can persist during drug treatment are a minor fraction of a tumour’s heterogenous cell composition and have been referred to as ‘cancer persisters’, which are thought to serve as reservoirs for cells to ultimately acquire full resistance to treatment. Understanding cancer persisters and how to overcome the emergence of drug resistance is of paramount importance to improve survival in melanoma patients otherwise succumbing to recurrent disease.

We developed an in vitro model of adaptive drug resistance, with a characteristic slow cycling early persister state across multiple cancer types including melanoma. To determine generic phenotypic and genomic traits, we conducted a series of studies including chromatin immunoprecipitation (ChIP), PCA-metabolomics and electron microscopy to investigate potential drivers for resistance. This inducible drug-tolerant state was reversible by removing exposure to treatment, and therefore not driven by any genetic mutations but was instead characterised by repressive epigenetic remodelling, heightened inflammatory signalling,  and metabolic adaptations of glycolytic and lipid pathways with features of stemness and senescence. Our findings provide novel insights into key biological alterations underpinning the development of adaptive drug resistance in melanoma.