Inhibition of glucose metabolism triggers targeted-therapy resistance in cultured BRAFV600E melanoma cells

Activating mutations in the BRAF oncogene are present in about 50% of melanoma, the most aggressive type of skin cancer. Treatment of patients bearing BRAF-mutated melanomas with BRAF-inhibitors (BRAFi) and MEK inhibitors (MEKi) leads initially to a favorable clinical response, but unfortunately more than 90% of tumors develop resistance to this “targeted therapy”, and relapse within one year. Thus, the identification of the driving mechanisms of BRAFi resistance is of paramount importance. BRAFi-resistant melanoma cells are characterized by (re)activation of oncogenic pathways capable to bypass the growth-inhibitory effects of BRAFi and/or reprogramming of their energetic metabolism. We have found that downregulation of Rictor (an essential component of the mTOR complex 2) in BRAFV600E melanoma cells is sufficient to induce resistance to BRAFi. Rictor-depleted cells do not display reactivation of MEK/ERK signaling in response to BRAFi, but exhibit metabolic features typical of BRAFi-resistant cells, including impaired glycolysis, a shift towards mitochondrial oxidative phosphorylation and enhanced activation of nicotinamide-phosphoribosyl-transferase, the rate limiting enzyme of NAD+ salvage pathway. Because mTORC2 is a positive regulator of glycolysis, I have hypothesized that Rictor depletion causes BRAFi/MEKi resistance, a least in part, by interfering with glucose metabolism. To test this hypothesis, I have used culture conditions in which BRAFV600E melanoma cells are forced to grow in the absence of glucose, and found that adapted cells rapidly develop BRAFi resistance. These findings may have therapeutic implications, as they suggest that interventions aimed to promote tumor glycolytic metabolism may oppose the development of therapeutic resistance in BRAF-mutated melanoma.