Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes.
Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes.
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DOI：
10.1038/s41388-021-02018-7
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发表时间：
2021-11
期刊：
影响因子：
8
通讯作者：
Prassolov V
中科院分区：
文献类型：
--
作者：
Lebedev T;Vagapova E;Spirin P;Rubtsov P;Astashkova O;Mikheeva A;Sorokin M;Vladimirova U;Suntsova M;Konovalov D;Roumiantsev A;Stocking C;Buzdin A;Prassolov V
与其他癌症相比，神经母细胞瘤（NB）的复发突变频率较低，这阻碍了靶向治疗和新的风险分层策略的发展。多激酶抑制剂已显示出治疗高风险NB的潜力，但它们的疗效可能会受到癌细胞通过采用替代信号通路适应这些药物的能力的影响。基于1189例NB肿瘤中48个生长因子相关基因的表达，我们建立了一个NB患者生存预测模型。该模型独立于MYCN扩增状态区分具有有利结局（>80%总存活率）和非常差结局（<10%）的4期NB肿瘤。在60名已知治疗反应的NB患者中使用信号通路分析和基因集富集方法，我们确定了在无反应或部分反应的患者中上调的信号通路，包括EPO、NGF和HGF。在治疗环境中，我们发现，在六种选定的生长因子中，EPO和NGF在体外对几种有前途的抗NB多激酶抑制剂显示出最明显的保护作用：伊马替尼，达沙替尼，克唑替尼，卡博替尼和阿西替尼。机制激酶抑制剂增强NB细胞更强的ERK激活EPO和NGF。这些生长因子的保护作用与ERK激活密切相关，并且是ERK依赖性的。ERK抑制剂与抗癌药物，特别是与达沙替尼联合使用，对NB细胞死亡显示出协同作用。考虑生长因子信号传导活性有利于NB结果预测和定制治疗方案以治疗NB。
Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.
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复发的神经母细胞瘤显示出频繁的RAS-MAPK途径突变。
影响因子：
30.8
作者：
Eleveld TF;Oldridge DA;Bernard V;Koster J;Colmet Daage L;Diskin SJ;Schild L;Bentahar NB;Bellini A;Chicard M;Lapouble E;Combaret V;Legoix-Né P;Michon J;Pugh TJ;Hart LS;Rader J;Attiyeh EF;Wei JS;Zhang S;Naranjo A;Gastier-Foster JM;Hogarty MD;Asgharzadeh S;Smith MA;Guidry Auvil JM;Watkins TB;Zwijnenburg DA;Ebus ME;van Sluis P;Hakkert A;van Wezel E;van der Schoot CE;Westerhout EM;Schulte JH;Tytgat GA;Dolman ME;Janoueix-Lerosey I;Gerhard DS;Caron HN;Delattre O;Khan J;Versteeg R;Schleiermacher G;Molenaar JJ;Maris JM
通讯作者：
Maris JM
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
影响因子：
9
作者：
通讯作者：
--
影响因子：
4.7
作者：
Lebedev, Timofey D.;Vagapova, Elmira R.;Prassolov, Vladimir S.
通讯作者：
Prassolov, Vladimir S.
影响因子：
7.7
作者：
Aikin, Timothy J.;Peterson, Amy F.;Regot, Sergi
通讯作者：
Regot, Sergi