Poster Presentation 35th Lorne Cancer Conference 2023

high fat diet modulates efficacy of BRAF/MEK targeted therapy in Melanoma (#105)

Shaghayegh Arabi 1 2 , Karen E Sheppard 1 2 , Grant A McArthur 1 2 , Laura Kirby 2
  1. Biochemistry, The University of Melbourne, Melbourne, VIC, Australia
  2. Peter MacCallum Cancer Centre, Essendon, VIC, Australia

Cutaneous melanoma is the most aggressive type of skin cancer and its global incidence rates are significantly increasing. Many recent therapeutic advances have been developed for the treatment of unresectable melanoma and have significantly improved survival in melanoma patients. Immune checkpoint inhibitors, and small molecule targeted therapies that decrease tumour cell proliferation and induce cell death through targeting BRAF and its downstream molecule MEK are currently standard of care treatment for melanoma patients. Despite these advancements in treatment there are many patients that fail to respond to immunotherapy or although most patients (~90%) initially respond to targeted therapy the majority eventually develop resistance to targeted therapies. With targeted therapy and due to the multitude of resistance mechanisms that develop, strategies to delay/or confine the development of resistance would be a clear game changer in the treatment of melanoma and provide a more universal and effective treatment. Interestingly, obesity and a high body mass index have been shown to significantly improve responses to both targeted and immunotherapy in male melanoma patients. Considering the metabolic abnormalities arising because of high body fat, improved BRAF/MEK targeted therapy efficacy following obesity is counterintuitive. The underlying mechanisms on how a high body mass index improves the efficacy of MAPK pathway targeted therapy in melanoma patients is unknown. Recently, we replicated the human data showing a highly significant increase in efficacy of BRAF/MEK inhibition in mice with excess adipose tissue as a result of a high fat diet. Our primary gene expression data have indicated that IFN receptor signaling may be important in the improved response to BRAF/MEK inhibition in mice. This study will address the mechanism(s) underpinning the association of high fat diet with improved outcomes to targeted therapy in melanoma by assessing tumour biological and transcriptional alterations. Finding the biological basis for this association will help to further understand how to improve the drug response without the adverse health effects related to being overweight. Finally, such information will help to develop novel therapeutic strategies that will improve the targeted therapy outcomes for melanoma patients.