Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma.
Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma.
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有效的BRAF抑制剂的发现使BRAF突变黑色素瘤的治疗发生了革命性的变化，但NRAS突变黑色素瘤仍然没有有效的治疗方法。由于RAS的直接药理抑制迄今尚未成功，我们探索了系统生物学方法来寻找能够模拟RAS直接抑制的协同药物组合(S)。在这里，利用一个可诱导的NRAS突变黑色素瘤小鼠模型，我们表明，与通过遗传手段在体内完全消除NRAS相反，药物抑制MEK激活了细胞凋亡，但未能触发细胞周期停滞。网络模型准确地指出CDK4是这种差异表型的关键驱动因素。因此，MEK和CDK4在体内的联合药理抑制在治疗效果上具有显著的协同作用。综上所述，我们的数据表明了一个致癌NRAS信号到典型MAPK级联的梯度模型，在那里，输出是门控的，导致离散的下游生物表型在不完全抑制的背景下去偶联。这种门控信号模型提供了一个新的框架，以确定在NRAS突变的黑色素瘤中联合药物抑制的非明显共消亡靶点(S)。
The discovery of potent BRAF inhibitors has revolutionized therapy for BRAF-mutant melanoma, yet NRAS-mutant melanoma remains without effective therapy. Since direct pharmacological inhibition of RAS has thus far been unsuccessful, we explored system biology approaches to identify synergistic drug combination(s) that can mimic direct RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological MEK inhibition activates apoptosis but fails to trigger cell cycle arrest, in contrast to complete NRAS extinction in vivo by genetic means. Network modeling pinpointed CDK4 as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to significant synergy in therapeutic efficacy. Taken together, our data suggest a gradient model of oncogenic NRAS signaling to the canonical MAPK cascade, where the output is gated, resulting in de-coupling of discrete downstream biological phenotypes in the setting of incomplete inhibition. Such a gated signaling model provides a novel framework to identify non-obvious co-extinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
82.9
作者：
通讯作者：
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全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
4.3
作者：
Packer, Leisl M.;East, Philip;Marais, Richard
通讯作者：
Marais, Richard