Biomedical Research in Melanoma-Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.
MAJ3 Capital S.L, Barcelona, 08018, Spain.
Nat Commun. 2022 Nov 19;13(1):7113. doi: 10.1038/s41467-022-34907-0.
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 NRAS-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 NRAS 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 NRAS-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.
NRAS 突变型黑色素瘤缺乏特定的治疗方法。代谢重编程被认为是控制癌症的一种新靶点；然而，NRAS 癌基因对这一癌症标志的贡献在很大程度上尚不清楚。在这里，我们表明，NRAS 突变型黑色素瘤的特定代谢状态介导了细胞对索拉非尼在代谢应激下的敏感性。从机制上讲，这些细胞依赖于葡萄糖代谢，葡萄糖剥夺会促进 CRAF 向 BRAF 信号转导的转变。这种情况有助于细胞存活，并通过 BRAF 介导的 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-2/3（PFKFB2/PFKFB3）的磷酸化来维持葡萄糖代谢。反过来，这有利于磷酸果糖激酶-1（PFK1）的变构激活，产生一个反馈回路，将糖酵解通量与 RAS 信号通路偶联。用 2-脱氧-D-葡萄糖（2-DG）和索拉非尼对 NRAS 突变型黑色素瘤（包括患者来源的异种移植物）进行体内治疗，可有效抑制肿瘤生长。因此，我们为 NRAS 癌基因对代谢重编程的贡献提供了证据，并为联合代谢应激（糖酵解抑制剂）和先前批准的药物（如索拉非尼）治疗 NRAS 突变型黑色素瘤提供了原理验证。
