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. While 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.

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致癌信号传导的矛盾激活作为癌症治疗策略

癌症稳态取决于驱动肿瘤发生的激活致癌途径与抵消此类异常信号传导固有毒性的应激反应程序之间的平衡。虽然致癌信号通路的抑制已被广泛探索，但越来越多的证据表明，相同通路的过度激活也会破坏癌症的稳态并导致死亡。我们在此表明​​，抑制蛋白磷酸酶 2A (PP2A) 会过度激活多种致癌途径并参与结肠癌细胞的应激反应。遗传和复合筛选发现，PP2A 和 WEE1 的联合抑制在多种癌症模型中具有协同作用，可破坏 DNA 复制并触发过早有丝分裂，随后导致细胞死亡。这种组合还抑制了体内患者源性肿瘤的生长。值得注意的是，对这种药物组合的获得性耐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，致癌信号传导的矛盾激活可能导致肿瘤抑制抵抗。