Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
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DOI：
10.1371/journal.pone.0163011
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Friedman R
中科院分区：
文献类型：
--
作者：
Buetti-Dinh A;O'Hare T;Friedman R
大量间变性大细胞淋巴瘤(ALCL)患者存在体细胞异常，间变性淋巴瘤激酶(ALK)与核磷蛋白(NPM)融合，产生具有结构性活性的信号融合蛋白NPM-ALK。我们通过计算模拟了通过NPM-ALK介导病理细胞生存和增殖的信号网络，以确定可能重新控制肿瘤发生过程的治疗靶点。这些模拟揭示了Vav1-CDc42(细胞分裂控制蛋白42)通路在NPM-ALK驱动的细胞增殖中的主要作用，以及Ras/丝裂原激活的ERK激酶(MEK)/细胞外信号调节激酶(ERK)级联在控制细胞存活中的主导作用。我们的结果也强调了一组白细胞介素组与Janus kinase3(JAK3)/信号转导和转录激活子3(STAT3)信号在NPM-ALK来源的ALCL的发展中的重要性。根据JAK3和STAT3的活性，该系统也可能对蛋白酪氨酸磷酸酶-1(SHP1)的激活敏感，SHP1对细胞的生存和增殖具有抑制作用。识别活跃在肿瘤发生过程中的信号通路对于有效的治疗是至关重要的。对避开经典治疗靶点的替代途径的预测，为对抗癌症耐药的出现开辟了预防方法。
A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.
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DOI：
10.1073/pnas.93.9.4181
发表时间：
1996-04-30
影响因子：
11.1
作者：
Fujimoto, J;Shiota, M;Yamamoto, T
通讯作者：
Yamamoto, T
影响因子：
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Ambrogio C;Voena C;Manazza AD;Martinengo C;Costa C;Kirchhausen T;Hirsch E;Inghirami G;Chiarle R
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Inghirami, G
DOI：
10.1158/1541-7786.mcr-13-0479-t
发表时间：
2014-01
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
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Varella-Garcia M
影响因子：
64.8
作者：
Albert, R;Jeong, H;Barabási, AL
通讯作者：
Barabási, AL