Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
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DOI：
10.1038/srep42604
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Fessel JP
中科院分区：
文献类型：
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作者：
Hardeman KN;Peng C;Paudel BB;Meyer CT;Luong T;Tyson DR;Young JD;Quaranta V;Fessel JP
代谢失调可以通过影响代偿信号传导和扩大细胞增殖来广泛影响治疗耐药性。鉴于许多BRAF突变的黑色素瘤患者使用靶向BRAF抑制剂后会出现疾病进展，我们假设治疗反应与肿瘤代谢表型有关，并且改变肿瘤代谢可能会改变治疗结果。我们证明了BRAF突变的黑色素瘤细胞用BRAF抑制剂PLX4720处理后的增殖动力学沿着敏感性谱下降，为研究代谢和药物敏感性的相互作用提供了一个模型系统。在主成分分析中，我们通过使用近12个代谢参数表征代谢表型，发现葡萄糖可用性与BRAF抑制敏感性之间存在反比关系。随后，我们产生了缺乏功能性线粒体呼吸和糖酵解代谢增加的rho0变异。与具有呼吸能力的亲本系相比，rho0细胞系对PLX4720的敏感性增加。最后，我们使用fda批准的抗逆转录病毒药物zalcitabine来抑制线粒体呼吸，并在我们的细胞系面板中强制糖酵解，通过改变EC50和Hill斜率指标来增加PLX4720的敏感性。我们的数据表明，在黑色素瘤中使用zalcitabine或其他类似方法强制肿瘤糖酵解可能是提高靶向BRAF治疗疗效的辅助手段。
Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.