BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy

Abstract

NRAS-mutated melanoma lacks a specific line of treatment. Metabolic reprogramming is considered a novel target to control cancer; however, NRAS-oncogene contribution to this cancer hallmark is mostly unknown. Here, we show that NRASQ61-mutated melanomas specific metabolic settings mediate cell sensitivity to sorafenib upon metabolic stress. Mechanistically, these cells are dependent on glucose metabolism, in which glucose deprivation promotes a switch from CRAF to BRAF signaling. This scenario contributes to cell survival and sustains glucose metabolism through BRAF-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2/3 (PFKFB2/PFKFB3). In turn, this favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop that couples glycolytic flux and the RAS signaling pathway. An in vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence for NRAS-oncogene contributions to metabolic rewiring and a proof-of-principle for the treatment of NRASQ61-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.

Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts

“…The response of cancer cells to glucose starvation has been extensively investigated by several previous studies, which highlighted multiple intrinsic mechanisms, in line with results of our study [ 53 – 57 ]. It is also important to underline that although here we focused on clones derived from established cancer cell lines, our group previously demonstrated that GDR/GDS populations exist also in OC patient-derived samples [ 58 ], thus underscoring the translational relevance of our findings.…”

Impact of Opioids on Cellular Metabolism: Implications for Metabolic Pathways Involved in Cancer

“…Despite being less efficient than OXPHOS, the Warburg effect, first described in 1920 by Otto Warburg, proposed that cancer cells preferentially upregulate glycolysis with lactate fermentation (potentially still in the presence of oxygen, hence the term aerobic glycolysis) to synthesize ATP [ 66 ]. This metabolic shift is initiated by several factors including the activation of oncogenes KRAS and BRAF, changes in the tumor microenvironment, and the inhibition of the tumor repressors NDRG2 and p53 [ 67 , 68 , 69 , 70 ]. Many cancer types overexpress GLUT (glucose transport) enzymes, particularly in hypoxic conditions, to accentuate cellular glucose uptake as a rate-limiting step of glycolysis [ 71 , 72 ].…”

Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer

“…Specifically, glycolytic metabolites fuel the biosynthesis of nucleosides and amino acids, essential for the synthesis of macromolecules required during proliferation. Moreover, glycolysis has been associated with the activation of signaling pathways involving proteins such as RAS (rat sarcoma virus oncogene), Myc (Myc proto-oncogene), TP53 (tumor protein suppressor p53), and HIF-1α (hypoxia inducible factor 1 subunit alpha), thereby promoting cancer development and progression [ 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, cancer cells display mitochondrial DNA mutations which induce mitochondrial dysfunction associated with tumor development, progression, and chemo-resistance.…”