Poster Presentation 35th Lorne Cancer Conference 2023

Characterizing the adaptive starvation response in melanoma cells treated with targeted therapies  (#104)

Arwa Alkaraki 1 2 , Kristin Brown 2 , Lorey Smith 2 , Karen Sheppard 2 , Grant McArthur 2
  1. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VICTORIA, Australia
  2. Cancer Research Department , Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Non-genetic adaptive mechanisms of acquired targeted therapy resistance have emerged as a barrier to curative treatment in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Indeed, early during adaptive resistance, a starved-like melanoma cell (SMC) state emerges that is characterized by downregulation of the overall cancer cell metabolic signature.They also upregulate other biomarkers of nutrient-starved cells including the fatty acid transporter CD36 and the amino acid transporter solute carrier family 7 member 8 , indicating altered nutrient usage may fuel SMC survival. Consistently, a role for fatty acid oxidation has been described during drug tolerance, but whether there is a role for reprogrammed amino acid metabolism, or if specific amino acids are essential for SMC survival, is not known. To determine the amino acid dependencies of drug tolerant melanoma cells following exposure to MAPK pathway targeted therapies we have optimised use of physiologically defined growth media, Plasmax. Our preliminary data indicates that Plasmax is a suitable model for assessing therapy response in BRAF mutant melanoma cells as it does not significantly alter proliferation rate, cellular morphology or sensitivity to MAPK pathway targeted therapies when compared to standard growth media RPMI.By performing an amino acid drop-out screen, our preliminary data shows that melanoma cells are using aspartate, glutamate and asparginine to fuel SMC cells, where we found depleting these amino acids significantly enhanced the MAPK pathway targeted therapy effect. Importantly, no significant effect on melanoma cells was seen with just the amino acid depletion suggesting these dependencies are specific to drug tolerant SMC cells.Understanding what cellular processes these amino acids are fuelling will give us a better understanding for the adaptive starvation response induced by MAPK targeted therapies in melanoma.This might lead to new strategies to eliminate drug tolerant cell populations and thereby prevent targeted therapy resistance