4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
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4E-BP1 是头颈癌中通过 mTOR 抑制重新激活的肿瘤抑制蛋白
DOI：
10.1158/0008-5472.can-18-1220
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发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
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作者：
Wang, Zhiyong;Feng, Xiaodong;Gutkind, J. Silvio
PI3K-mTOR 信号通路的异常激活发生在超过 80% 的头颈鳞状细胞癌 (HNSCC) 中，过度依赖该信号通路可能反过来代表了一种可用于治疗的癌症特异性脆弱性。 mTOR 抑制剂 (mTORi) 在基因定义和化学诱导的 HNSC 动物模型中促进肿瘤消退，最近报道了令人鼓舞的结果。然而，mTOR 调节的有助于临床反应的靶点尚未确定。在这里，我们重点关注 EIF4E-BP1 (4E-BP1)，它是 mTOR 的直接靶点，是蛋白质合成的关键效应子。对 HNSCC PIK3CA-mTOR 通路基因组改变的系统分析表明，4E-BP1 很少发生突变，但超过 35% 的 HNSCC 患者至少丢失一个 4E-BP1 基因拷贝，与 4E-BP1 蛋白表达下降相关。 4E-BP1 基因拷贝数丢失与较差的无病生存率和总生存率相关。与肿瘤抑制作用相一致，4e-bp1/2 基因敲除小鼠在 HNSCC 癌变模型中形成更大、更多的病变。 mTORi 治疗或条件表达不能被 mTOR 磷酸化的突变体 4EBP1 足以破坏翻译起始复合物并阻止肿瘤生长。此外，CRISPR/Cas9 靶向的 4E-BP1 HNSCC 细胞导致体外和体内对 mTORi 的敏感性降低。总的来说，这些研究结果表明，在 HNSCC 中，mTOR 通过磷酸化持续抑制 4E-BP1，并且 mTORi 可以恢复 4E-BP1 的肿瘤抑制功能。我们的研究结果还支持 4E-BP1 表达和磷酸化状态作为 HNSCC 患者 mTORi 敏感性的机械生物标志物。意义：这些发现表明 EIF4E-BP1 在 HNSCC 中充当肿瘤抑制因子，4E-BP1 去磷酸化介导对 mTORi 的治疗反应，为未来的精准肿瘤学试验提供机械生物标志物。
Aberrant activation of the PI3K-mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTORinhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCCanimal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on EIF4E-BP1 (4E-BP1), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the PIK3CA-mTOR pathway in HNSCC revealed that 4E-BP1 is rarely mutated, but at least one 4E-BP1 gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. 4E-BP1 gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, 4e-bp1/2 knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4EBP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation-initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9-targeted 4E-BP1 HNSCC cells resulted in reduced sensitivity to mTORi in vitro and in vivo. Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC.Significance: These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.