Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors
Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors
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DOI：
10.1158/0008-5472.can-07-6720
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Ji, Qun-Sheng
中科院分区：
文献类型：
--
作者：
Buck, Elizabeth;Eyzaguirre, Alexandra;Ji, Qun-Sheng
表皮生长因子受体（EGFR）和胰岛素样生长因子-I受体（IGF-IR）可协同调节肿瘤生长和存活，联合阻断EGFR和IGF-IR可协同抑制肿瘤生长，但在临床前模型中，只有一部分肿瘤对该联合治疗表现出高敏感性，因此需要对患者进行筛选以优化临床疗效。在此，我们已经表征了EGFR和IGF-IR双重阻断后协同生长抑制的分子基础，并提供了似乎区分反应的生物标志物。我们发现，上皮细胞，但不是间充质样，肿瘤细胞，Akt是由EGFR和IGF-IR的协同控制。这与协同细胞凋亡和生长抑制在体外和生长消退在体内联合阻断两种受体。我们确定了两个有助于协同作用的分子方面：（a）EGFR或IGF-IR的抑制单独促进相互受体的激活;（B）EGFR指导的促分裂原活化蛋白激酶（MAPK）的抑制将Akt的调节从EGFR转移到IGF-IR。通过下游MAPK/细胞外信号调节激酶激酶（MEK）拮抗作用靶向MAPK途径类似地促进IGF驱动的pAkt和与IGF-1 R的协同作用。IR抑制。从机制上讲，我们发现MAPK通路的抑制绕过了施加在IGF-IR-胰岛素受体底物I（IRS-1）信号传导复合物上的负反馈回路，这是一种与介导雷帕霉素介导的IGF-IR信号传导的mTOR-p70 S6 K和IRS-1之间的负反馈回路平行的分子情况。总的来说，这些数据表明对MEK、mTOR和EGFR抑制的抗性与增强的IGF-IR导向的Akt信号传导相关，其中所有影响在IRS-1水平会聚的反馈环。[Cancer Res 2008;68（20）：8322-32]
Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic growth inhibition has been reported for combined blockade of EGFR and IGF-IR. However, in preclinical models, only a subset of tumors exhibit high sensitivity to this combination, highlighting the potential need for patient selection to optimize clinical efficacy. Herein, we have characterized the molecular basis for cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide biomarkers that seem to differentiate response. We find for epithelial, but not for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in vitro and growth regression in vivo upon combined blockade of both receptors. We identified two molecular aspects contributing to synergy: (a) inhibition of EGFR or IGF-IR individually promotes activation of the reciprocal receptor; (b) inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. Mechanistically, we find that inhibition of the MAPK pathway circumvents a negative feedback loop imposed on the IGF-IR- insulin receptor substrate I (IRS-1) signaling complex, a molecular scenario that parallels the negative feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed IGF-IR signaling. Collectively, these data show that resistance to inhibition of MEK, mTOR, and EGFR is associated with enhanced IGF-IR-directed Akt signaling, where all affect feedback loops converging at the level of IRS-1. [Cancer Res 2008;68(20):8322-32]