EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.
EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.
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DOI：
10.1158/1535-7163.mct-17-0137
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发表时间：
2018-05
影响因子：
5.7
通讯作者：
Amatruda JF
中科院分区：
文献类型：
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作者：
Chen KS;Fustino NJ;Shukla AA;Stroup EK;Budhipramono A;Ateek C;Stuart SH;Yamaguchi K;Kapur P;Frazier AL;Lum L;Looijenga LHJ;Laetsch TW;Rakheja D;Amatruda JF
生殖细胞肿瘤(GCTS)是一种起源于多能胚胎生殖细胞的恶性肿瘤，见于儿童和年轻人。GCTS采用以顺铂为基础的治疗方案，虽然总体有效，但不能治愈所有患者，并导致显著的不良后遗症。精原细胞瘤和非精原细胞瘤具有不同的分化状态、临床表现和治疗反应，但GCT分化的分子机制尚不完全清楚。我们测试了哺乳动物靶标雷帕霉素复合体1(MTORC1)和丝裂原活化蛋白激酶(MAPK)通路在这两类GCT中的活性是否存在差异。在这里，我们发现来自儿童和成人的非精原细胞瘤性生殖细胞肿瘤(NSGCT，包括胚胎癌、卵黄囊肿瘤和绒毛膜癌)都表现出mTORC1通路的激活，而精原细胞瘤则不激活。在精原细胞瘤中，高水平的Redd1可能负向调节mTORC1的活性。另一方面，在NSGCT中，EGF和FGF2配体可以刺激mTORC1和MAPK信号转导，EGF和FGF2受体家族成员的表达更高。最后，分别针对EGFR和mTORC1信号通路的临床可用药物厄洛替尼和雷帕霉素联合治疗NSGCT细胞，可显著抑制NSGCT细胞的体内外增殖。这些结果提供了对驱动GCT生长的信号网络的理解，并为使用拮抗EGFR和mTORC1通路的药物治疗GCTS提供了理论基础。
Germ cell tumors (GCTs) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and non-seminoma forms of GCT exhibit distinct differentiation states, clinical behavior and response to treatment, however the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) pathways were differentially active in the two classes of GCT. Here we show that non-seminomatous germ cell tumors (NSGCTs, including embryonal carcinoma, yolk sac tumor and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Lastly, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways.