Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H S Wilms, Marcelo S da Silva, Robin A Jansen, Antonio Mulero-Sánchez, Elke Malzer, August Vidal, Cristina Santos, Ramón Salazar, Rosangela A M Wailemann, Thompson E P Torres, Giulia De Conti, Jonne A Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S Kovach, Hugo A Armelin, Hein Te Riele, Alexander van Oudenaarden, Haojie Jin, Roderick L Beijersbergen, Alberto Villanueva, Rene H Medema, Rene Bernards
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引用次数: 0
摘要
癌症的稳态取决于驱动肿瘤发生的致癌通路激活与应激反应程序参与之间的平衡,应激反应程序可抵消这种异常信号传导的固有毒性。尽管抑制致癌信号通路的研究已经非常广泛,但越来越多的证据表明,过度激活同样的通路也会破坏癌症稳态并导致死亡。我们在此表明,抑制蛋白磷酸酶 2A(PP2A)会过度激活多种致癌通路,并使结肠癌细胞产生应激反应。通过基因和化合物筛选发现,联合抑制 PP2A 和 WEE1 在多种癌症模型中具有协同作用,能使 DNA 复制崩溃并引发过早的有丝分裂,继而导致细胞死亡。这种组合还能抑制患者体内肿瘤的生长。值得注意的是,获得性抗药性抑制了结肠癌细胞在体内形成肿瘤的能力。我们的数据表明,致癌信号的悖论性激活可导致抑制肿瘤的抗药性。
Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.
Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.