Grillo Elisabetta, Corsini Michela, Ravelli Cosetta, Zammataro Luca, Bacci Marina, Morandi Andrea, Monti Eugenio, Presta Marco, Mitola Stefania
Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy.
Cancer Lett. 2021 Jun 1;507:80-88. doi: 10.1016/j.canlet.2021.03.007. Epub 2021 Mar 17.
Vascular endothelial growth factor receptor 2 (VEGFR2) activating mutations are emerging as important oncogenic driver events. Understanding the biological implications of such mutations may help to pinpoint novel therapeutic targets. Here we show that activated VEGFR2 via the pro-oncogenic R1051Q mutation induces relevant metabolic changes in melanoma cells. The expression of VEGFR2 leads to higher energy metabolism and ATP production compared to control cells expressing VEGFR2. Furthermore, activated VEGFR2 augments the dependence on glutamine (Gln) of melanoma cells, thus increasing Gln uptake and their sensitivity to Gln deprivation and to inhibitors of glutaminase, the enzyme initiating Gln metabolism by cells. Overall, these results highlight Gln addiction as a metabolic vulnerability of tumors harboring the activating VEGFR2 mutation and suggest novel therapeutic approaches for those patients harboring activating mutations of VEGFR2.
血管内皮生长因子受体2（VEGFR2）激活突变正逐渐成为重要的致癌驱动事件。了解此类突变的生物学意义可能有助于确定新的治疗靶点。在此，我们表明，通过致癌性R1051Q突变激活的VEGFR2会在黑色素瘤细胞中诱导相关的代谢变化。与表达VEGFR2的对照细胞相比，VEGFR2的表达导致更高的能量代谢和ATP产生。此外，激活的VEGFR2增强了黑色素瘤细胞对谷氨酰胺（Gln）的依赖性，从而增加了Gln摄取以及它们对Gln剥夺和谷氨酰胺酶抑制剂的敏感性，谷氨酰胺酶是细胞启动Gln代谢的酶。总体而言，这些结果突出了Gln成瘾是携带激活型VEGFR2突变肿瘤的一种代谢脆弱性，并为那些携带VEGFR2激活突变的患者提出了新的治疗方法。
