Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.
Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.
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DOI：
10.1158/2159-8290.cd-13-0440
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发表时间：
2014-04
期刊：
影响因子：
28.2
通讯作者：
McArthur GA
中科院分区：
文献类型：
--
作者：
Parmenter TJ;Kleinschmidt M;Kinross KM;Bond ST;Li J;Kaadige MR;Rao A;Sheppard KE;Hugo W;Pupo GM;Pearson RB;McGee SL;Long GV;Scolyer RA;Rizos H;Lo RS;Cullinane C;Ayer DE;Ribas A;Johnstone RW;Hicks RJ;McArthur GA
解除调节的葡萄糖代谢满足了癌基因驱动的肿瘤生长的能量和生物合成要求。由于抑制致癌的BRAF导致葡萄糖摄取的显著减少和对BRAF突变黑色素瘤的强烈临床益处，我们研究了能量代谢在BRAF抑制反应中的作用。我们观察到BRAF突变黑色素瘤细胞的糖酵解活性显著和持续下降。此外，我们确定了一个由BRAF调节的转录因子网络，这些转录因子控制着黑色素瘤细胞中的糖酵解。值得注意的是，这个转录因子网络，包括HIF1α，c-Myc和MondoA，驱动BRAFV600下游的糖酵解，对于对BRAF抑制的反应是关键的，并受到临床黑色素瘤标本BRAF抑制的调节。此外，我们发现同时抑制BRAF和糖酵解可以诱导耐BRAF抑制剂的黑色素瘤细胞死亡。因此，我们提供了用BRAF抑制剂和糖酵解抑制剂联合治疗黑色素瘤的原则证据。
Deregulated glucose metabolism fulfils the energetic and biosynthetic requirements for tumour growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including HIF1α, c-Myc and MondoA, drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor-resistant melanoma cells. Thus, we provide a proof of principle for treatment of melanoma with combinations of BRAF inhibitors and glycolysis inhibitors.