Table 1.

Impact of Oncogenic Signaling Pathways on Melanoma Metabolism

Signaling Pathway	Alterations in Melanoma	Metabolic Effects
MAPK	• Constitutive activity due to point mutations in BRAF (35–50%) and NRAS (10–25%) and deletions in NF1 (~15%)	Suppresses MITF and PGC1α to inhibit OXPHOS Stimulates MYC and HIF1α signaling to promote glycolysis Also promotes fatty acid synthesis
PI3K-AKT	Loss of function of PTEN (30–50%) Point mutations in PI3K (<3%) Point mutations in AKT (<3%) Point mutations in NRAS (10–25%)	Stimulates MYC and HIF1α signaling to promote aerobic glycolysis Promotes aerobic glycolysis and fatty acid synthesis Stimulates mTOR to promote OXPHOS in a subset of melanomas
mTOR	mTORC1 and 2 activated by PI3K-AKT pathway mTORC1 stimulated in response to amino acids mTORC1 suppressed by AMPK in response to ↑AMP/ATP	Drives transcription of HIF1α and MYC, promoting aerobic glycolysis Promotes fatty acid synthesis, protein synthesis, and nucleotide synthesis Promotes translocation of MITF to the nucleus, promoting PGC1α expression and OXPHOS in a subset of melanomas
HIF1α	Degradation inhibited by hypoxia and ROS Transcription/translation promoted by MAPK pathway signaling, and translation promoted by PI3K pathway signaling	Stimulates aldolase, ENO1, LDH, which directly promote glycolytic flux Activates PDK, preventing the flow of pyruvate into the TCA cycle Promotes DEC1 activity, indirectly inhibiting OXPHOS
MYC	Activated by pERK Copy number gains (~30% of metastatic melanomas)	Drives GLUT1, HK2, and LDH transcription, promoting aerobic glycolysis Promotes glutaminase transcription, stimulating glutamine metabolism
MITF	MITF inhibited by pERK MITF transcription suppressed by HIF1α and DEC1 MITF transcription promoted by PGC1α PGC1α transcription promoted by LKB1-AMPK axis	Promotes OXPHOS
LKB1-AMPK	LKB1 responds to ↑AMP/ATP ratio by activating AMPK	AMPK inhibits mTOR activity and biosynthetic reactions; promotes PGC1α transcription and OXPHOS