Background/Aims
After BRAF, NRAS is the most commonly mutated oncogene in melanoma. However therapies targeting NRAS remain elusive. Recent investigations have demonstrated that mutated RAS can increase glycolytic metabolism in cancer cells, and our previous work1 has elucidated a role for glycolysis in responses to inactivation of BRAF. This study aims to compare and contrast NRAS- versus BRAF-driven glycolysis in melanoma, in the setting of targeted therapies.
Methods
A panel of NRAS and BRAF-mutant melanoma cell lines were screened for changes in viability and glycolysis following treatment with a panel of small molecule inhibitors targeting the MAPK and PI3K pathways. Glycolytic responses of melanoma cells, following MEK, ERK, PI3K or mTOR inhibition (alone or in combination), were investigated by assessing cell proliferation, glucose uptake, lactate production, and known transcriptional regulators of glycolysis.
Results
In NRAS-mutant melanoma, MEK and ERK inhibition resulted in a reduction in lactate production, and similar responses were observed following treatment with mTORC1/2 and PI3K/mTOR inhibitors but not AKT or selective PI3K inhibitors. Treatment with MEK or ERK inhibitors resulted in a consistent reduction in glucose uptake, with a more modest effect being observed following combined PI3K/mTOR inhibition. Notably, treatment with these inhibitors also resulted in altered expression of transcriptional regulators of glycolysis (reduced MYC and HIF1a, increased TXNIP protein expression), similar to that seen in BRAF-mutant melanoma cells. The effect of combined pathway inhibition on glycolysis is currently under investigation.
Conclusion
NRAS-mutant melanoma cells demonstrate a similar glycolytic phenotype to BRAF-mutant melanoma cells, with MAPK pathway and mTOR inhibition resulting in decreased lactate production, glucose uptake and modulation of a network of transcriptional regulators of glycolysis. These findings highlight the importance of oncogene-driven glycolysis in melanoma, and the need for further investigation into glycolysis as a therapeutic target in the treatment of patients with NRAS-mutant melanoma.