Oral Presentation 2nd Australian Cancer and Metabolism Meeting 2017

Investigating therapeutic strategies targeting metabolism in NRAS-mutant melanoma (#22)

Aparna D Rao 1 2 , Lorey K Smith 1 , Tiffany J Parmenter 1 , Rachael Walker 3 , Jeanette Schreuders 3 , Tariq Butt 4 , Tony Tiganis 4 , Carleen Cullinane 3 , Philip Hogg 5 , Grant A McArthur 1 2 6
  1. Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  3. Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Monash University, Clayton, VIC, Australia
  5. ACRF-Centenary Cancer Research Centre, University of Sydney, Camperdown, NSW, Australia
  6. Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia

Background

After BRAF, NRAS is the most commonly mutated oncogene in melanoma. However therapies targeting NRAS remain elusive. In BRAF-mutant melanoma cells, BRAF inhibitors suppress glycolysis, and induce mitochondrial metabolism, through expression of MITF and PGC1a. We hypothesised that addition of a mitochondrial inhibitor (PENAO) would enhance the efficacy of the MEK inhibitor trametinib in NRAS-mutant melanoma models.

 

Materials and Methods

The responses of NRAS-mutant melanoma cells, to MAPK pathway and mitochondrial inhibition, were investigated by assessing: cell proliferation; lactate production; glucose uptake; gene expression profiles of metabolic regulators and extracellular flux analysis. An IPC298 NRAS-mutant melanoma xenograft model was used to study the inhibitors in vivo.

 

Results

In NRAS-mutant melanoma cells, MEK and ERK inhibition resulted in reduced glucose uptake and lactate production; and increased MITF and PGC1a expression. In NRAS-mutant melanoma cells, the addition of PENAO to trametinib enhanced the effect on cellular proliferation. Extracellular flux analysis showed a reduction in extracellular acidification rate following trametinib; reduced oxygen consumption rate after PENAO and a reduction in both parameters with the combination. In vivo, the addition of PENAO was well tolerated but did not enhance the anti-proliferative effect of trametinib.

 

Conclusion

In NRAS-mutant melanoma cells, MAPK pathway inhibition results in metabolic reprogramming similar to changes observed in BRAF-mutant melanoma cells. The addition of PENAO to trametinib results in altered metabolic reprogramming and enhances anti-proliferative activity in vitro. Further studies to investigate differences between the in vitro and in vivo models are currently underway.