Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina and Escola de Artes, Ciências e Humanidades; University of São Paulo, São Paulo, Brazil.
Elife. 2021 May 11;10:e59696. doi: 10.7554/eLife.59696.
Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically relevant strategy for anti-metastatic treatment.
由于网络异质性和代偿性网络激活，高剂量、多药物靶向治疗转移抑制的效果并不成功。在这里，我们表明，通过有限抑制核心途径来靶向驱动网络信号转导能力是一种更有效的抗转移策略。该原理是基于一种生理转移抑制剂 Raf 激酶抑制蛋白 (RKIP) 的作用，它适度降低应激调节的 MAP 激酶网络活性，减少转录因子（如促转移的 BACH1 和运动相关靶基因）的输出。我们开发了一种低剂量的四药模拟物，可阻止小鼠乳腺癌模型中的转移定植并提高生存率。实验和网络流建模表明，需要有限抑制多种途径来克服 MAPK 网络拓扑的变化，并抑制异质肿瘤细胞中的信号转导输出。限制对单个激酶的抑制会消耗多余的信号，防止补偿性激酶网络的阈值激活。这种降低驱动网络信号转导能力的低剂量多药物方法代表了一种变革性的、具有临床相关性的抗转移治疗策略。
