Systems Biology Modeling Reveals a Possible Mechanism of the Tumor Cell Death upon Oncogene Inactivation in EGFR Addicted Cancers

Despite many evidences supporting the concept of “oncogene addiction” and many hypotheses rationalizing it, there is still a lack of detailed understanding to the precise molecular mechanism underlying oncogene addiction. In this account, we developed a mathematic model of epidermal growth factor receptor (EGFR) associated signaling network, which involves EGFR-driving proliferation/pro-survival signaling pathways Ras/extracellular-signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K)/AKT, and pro-apoptotic signaling pathway apoptosis signal-regulating kinase 1 (ASK1)/p38. In the setting of sustained EGFR activation, the simulation results show a persistent high level of proliferation/pro-survival effectors phospho-ERK and phospho-AKT, and a basal level of pro-apoptotic effector phospho-p38. The potential of p38 activation (apoptotic potential) due to the elevated level of reactive oxygen species (ROS) is largely suppressed by the negative crosstalk between PI3K/AKT and ASK1/p38 pathways. Upon acute EGFR inactivation, the survival signals decay rapidly, followed by a fast increase of the apoptotic signal due to the release of apoptotic potential. Overall, our systems biology modeling together with experimental validations reveals that inhibition of survival signals and concomitant release of apoptotic potential jointly contribute to the tumor cell death following the inhibition of addicted oncogene in EGFR addicted cancers.

尽管已有诸多证据支持“癌基因成瘾（oncogene addiction）”这一概念，且已有诸多假说对其合理性进行阐释，但目前学界对癌基因成瘾背后的精确分子机制仍缺乏详尽认知。本研究构建了与表皮生长因子受体（EGFR）相关的信号网络数学模型，该网络涵盖EGFR驱动的增殖/促存活信号通路——Ras/细胞外调节蛋白激酶（ERK）与磷脂酰肌醇3-激酶（PI3K）/AKT，以及促凋亡信号通路凋亡信号调节激酶1（ASK1）/p38。在EGFR持续激活的场景下，仿真结果显示增殖/促存活效应分子磷酸化ERK与磷酸化AKT维持在较高水平，而促凋亡效应分子磷酸化p38则处于基础水平。由活性氧（ROS）水平升高所介导的p38激活潜能（即凋亡潜能），因PI3K/AKT与ASK1/p38通路间的负向串扰而被大幅抑制。当EGFR发生急性失活时，存活信号会快速衰减，随后凋亡潜能的释放会引发凋亡信号的快速升高。综上，本研究的系统生物学建模（systems biology modeling）结合实验验证结果表明：在EGFR成瘾型癌症中，抑制成瘾性癌基因后，存活信号的阻断与凋亡潜能的协同释放共同促成了肿瘤细胞的死亡。