mTOR kinase inhibition disrupts neuregulin 1-ERBB3 autocrine signaling and sensitizes NF2-deficient meningioma cellular models to IGF1R inhibition.
mTOR kinase inhibition disrupts neuregulin 1-ERBB3 autocrine signaling and sensitizes NF2-deficient meningioma cellular models to IGF1R inhibition.
复制标题
DOI：
10.1074/jbc.ra120.014960
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Ramesh V
中科院分区：
文献类型：
--
作者：
Beauchamp RL;Erdin S;Witt L;Jordan JT;Plotkin SR;Gusella JF;Ramesh V
脑膜瘤（MN），起源于蛛网膜/脑膜层，对化疗无反应，约50%显示神经纤维瘤病2（NF 2）肿瘤抑制基因的丢失。之前，我们建立了NF 2损失激活雷帕霉素复合物1（mTORC 1）和雷帕霉素复合物2（mTORC 2）信号传导的机制靶点，导致NF 2和MN的临床试验。最近，我们的组学研究确定了激活肝配蛋白（EPH）受体和Src家族激酶的NF 2损失。在这里，我们报告了在NF 2-空人类蛛网膜细胞（AC）和MN细胞系Ben-Men-1，特别是neuregulin-1/heregulin（NRG 1）的几个配体的表达增加，并确认增加NRG 1分泌和激活V-ER B-B禽成红细胞白血病病毒癌基因同源物3（ERBB 3）受体激酶。来自NF 2无效AC或外源NRG 1的条件培养基刺激ERBB 3、EPHA 2和mTORC 1/2信号传导，表明通路串扰。用ERBB 3中和抗体处理的NF 2-null细胞部分下调mTOR途径活化，但对活力无影响。mTORC 1/2抑制剂处理降低了NRG 1表达并下调了ERBB 3，同时重新激活了pAkt T308，表明其机制独立于NRG 1-ERBB 3，但可能涉及另一种上游受体激酶的激活。mTORC 1/2抑制后的转录组学证实ERBB 3/ERBB 4降低，同时显示胰岛素样生长因子受体1（IGF 1 R）表达增加。共靶向mTORC 1/2和IGF 1 R/胰岛素受体的药物治疗减弱了pAkt T308，并显示出对活力的协同作用。我们的研究结果表明，潜在的自分泌信号，其中NF 2的损失导致NRG 1-ERBB 3信号的分泌/激活。mTORC 1/2抑制下调NRG 1-ERBB 3，同时通过涉及IGF 1 R/胰岛素受体的适应性反应上调pAkt T308，并共同靶向这些途径可能被证明对治疗NF 2缺陷型MN有效。
Meningiomas (MNs), arising from the arachnoid/meningeal layer, are nonresponsive to chemotherapies, with ∼50% showing loss of the Neurofibromatosis 2 (NF2) tumor suppressor gene. Previously, we established NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mechanistic target of rapamycin complex 2 (mTORC2) signaling, leading to clinical trials for NF2 and MN. Recently our omics studies identified activated ephrin (EPH) receptor and Src family kinases upon NF2 loss. Here, we report increased expression of several ligands in NF2-null human arachnoidal cells (ACs) and the MN cell line Ben-Men-1, particularly neuregulin-1/heregulin (NRG1), and confirm increased NRG1 secretion and activation of V-ERB-B avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor kinase. Conditioned-medium from NF2-null ACs or exogenous NRG1 stimulated ERBB3, EPHA2, and mTORC1/2 signaling, suggesting pathway crosstalk. NF2-null cells treated with an ERBB3-neutralizing antibody partially downregulated mTOR pathway activation but showed no effect on viability. mTORC1/2 inhibitor treatment decreased NRG1 expression and downregulated ERBB3 while re-activating pAkt T308, suggesting a mechanism independent of NRG1–ERBB3 but likely involving activation of another upstream receptor kinase. Transcriptomics after mTORC1/2 inhibition confirmed decreased ERBB3/ERBB4 while revealing increased expression of insulin-like growth factor receptor 1 (IGF1R). Drug treatment co-targeting mTORC1/2 and IGF1R/insulin receptor attenuated pAkt T308 and showed synergistic effects on viability. Our findings indicate potential autocrine signaling where NF2 loss leads to secretion/activation of NRG1-ERBB3 signaling. mTORC1/2 inhibition downregulates NRG1-ERBB3, while upregulating pAkt T308 through an adaptive response involving IGF1R/insulin receptor and co-targeting these pathways may prove effective for treatment of NF2-deficient MN.