Abstract

Melanoma is a deadly skin cancer linked to ultraviolet radiation (UVR) and genome sequencing reveals a landscape replete in mutations associated with this environmental insult.   Various subtypes of melanoma are defined by their driver oncogenes; BRAF is mutated in half of common cutaneous melanomas, and NRAS in another 20% of cases.  BRAF and MEK (activated by BRAF) drugs extend patient survival in BRAF mutant melanoma patients, but are less effective in NRAS melanomas signalling re-routes through other pathways to bypass BRAF and MEK inhibition.  Separately, drugs that activate the immune system are effective in 20-60% and can lead to cure independent of the driver oncogene.  The paradigm shift in melanoma care driven by these new drugs has increased patient survival, but most patients still die of their disease.  Acquired and innate resistance limits responses to targeted therapies and it is unclear how patients should be stratified for immunotherapies.  We are using mouse models to examine the relationship between oncogenes and UVR in melanomagenesis and to understand what determines responses to new drugs.  Separately, we are using cell-free tumour DNA (ctDNA) in patient circulation to monitor responses to targeted and immunotherapies to adjust treatment and achieve better patient outcomes.