The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to over-come this, we identified LINC00518 (LENOX; lincR NA -enhancer of oxidative phosphorylation) as a melanoma -specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxida-tive phosphorylation. LENOX expression was upregulated fol-lowing treatment with MAPK inhibitors, facilitating a meta-bolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, com-bined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression.Significance: The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.