Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.
Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.
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DOI：
10.1016/j.radonc.2014.04.010
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Willey CD
中科院分区：
文献类型：
--
作者：
Anderson JC;Duarte CW;Welaya K;Rohrbach TD;Bredel M;Yang ES;Choradia NV;Thottassery JV;Yancey Gillespie G;Bonner JA;Willey CD
多形性胶质母细胞瘤（GBM）是最常见和致命的原发性脑恶性肿瘤，特别是由于替莫唑胺（TMZ）和放射（RT）抗性。为了更好地理解抗性机制，我们检查了治疗敏感性和抗性人GBM患者来源的异种移植物（PDX或“Xenolines”）中的整体激酶活性（激酶组学分析）。检查了13个原位植入的xenolines，其中8个具有已知的RT敏感性/抗性，而5个TMZ抗性xenolines通过体内连续TMZ处理产生。收获肿瘤，制备为总蛋白裂解物，并在PamStation®12高通量微阵列平台上进行动力学分析，随后进行上游激酶预测和网络建模。激酶谱表明与辐射抗性表型相关的酪氨酸激酶活性升高，包括FAK和FGFR 1。此外，网络建模显示可能涉及VEGFR 1/2和c-Raf枢纽。获得性TMZ耐药分析显示TMZ耐药肿瘤中存在更多的激酶组变异性。在TMZ耐药的Xenolines中，5个肿瘤中有2个显示出显著改变的激酶活性，网络建模表明PKC、JAK 1、PI 3 K、CDK 2和VEGFR是这种耐药的潜在介质。GBM Xenolines提供了GBM药物应答和抗性的表型模型，当与kinomic分析配对时，其鉴定了固有（辐射）或获得性（TMZ）抗性的靶向途径。
Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or “xenolines”). Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.
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影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
基于途径的微阵列分析中的误差控制变异性。
DOI：
10.1093/bioinformatics/btp385
发表时间：
2009-09-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gold DL;Miecznikowski JC;Liu S
通讯作者：
Liu S
影响因子：
27.4
作者：
Umiċeviċ Mirkov M;Cui J;Vermeulen SH;Stahl EA;Toonen EJ;Makkinje RR;Lee AT;Huizinga TW;Allaart R;Barton A;Mariette X;Miceli CR;Criswell LA;Tak PP;de Vries N;Saevarsdottir S;Padyukov L;Bridges SL;van Schaardenburg DJ;Jansen TL;Dutmer EA;van de Laar MA;Barrera P;Radstake TR;van Riel PL;Scheffer H;Franke B;Brunner HG;Plenge RM;Gregersen PK;Guchelaar HJ;Coenen MJ
通讯作者：
Coenen MJ
影响因子：
45.3
作者：
Hegi, Monika E.;Liu, Lili;Gilbert, Mark R.
通讯作者：
Gilbert, Mark R.
影响因子：
5.7
作者：
Jarboe, John S.;Jaboin, Jerry J.;Willey, Christopher D.
通讯作者：
Willey, Christopher D.