The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma.
The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma.
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DOI：
10.1016/j.ccr.2012.06.001
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发表时间：
2012-07-10
期刊：
影响因子：
50.3
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Berry T;Luther W;Bhatnagar N;Jamin Y;Poon E;Sanda T;Pei D;Sharma B;Vetharoy WR;Hallsworth A;Ahmad Z;Barker K;Moreau L;Webber H;Wang W;Liu Q;Perez-Atayde A;Rodig S;Cheung NK;Raynaud F;Hallberg B;Robinson SP;Gray NS;Pearson AD;Eccles SA;Chesler L;George RE
ALKF 1174 L突变与神经母细胞瘤中对克唑替尼的内在和获得性耐药相关，并与MYCN共分离。在这项研究中，我们建立了一个在神经嵴中过表达ALKF 1174 L的小鼠模型。与单独的ALKF 1174 L和MYCN相比，这两种癌基因的共表达导致神经母细胞瘤的发展，具有更早的发病率，更高的转移率和更高的致死率。ALKF 1174 L/MYCN肿瘤由于ALKF 1174 L诱导的PI 3 K/AKT/mTOR和MAPK通路激活以及MYCN促凋亡作用抑制而显示MYCN剂量增加。与ATP竞争性mTOR抑制剂Torin 2联合治疗克服了ALKF 1174 L/MYCN肿瘤对克唑替尼的耐药性。我们的研究结果证明了ALKF 1174 L在过度表达MYCN的神经母细胞瘤中的致病作用，并提出了改善ALK阳性神经母细胞瘤靶向治疗的策略。
The ALKF1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALKF1174L in the neural crest. Compared to ALKF1174L and MYCN alone, coexpression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance and enhanced lethality. ALKF1174L/MYCN tumors exhibited increased MYCN dosage due to ALKF1174L-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN pro-apoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2, overcame the resistance of ALKF1174L/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALKF1174L in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.
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DOI：
10.1056/nejmoa1007056
发表时间：
2010-10-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Butrynski JE;D'Adamo DR;Hornick JL;Dal Cin P;Antonescu CR;Jhanwar SC;Ladanyi M;Capelletti M;Rodig SJ;Ramaiya N;Kwak EL;Clark JW;Wilner KD;Christensen JG;Jänne PA;Maki RG;Demetri GD;Shapiro GI
通讯作者：
Shapiro GI
影响因子：
45.3
作者：
Cohn, SL;London, WB;Haber, M
通讯作者：
Haber, M
影响因子：
50.3
作者：
Murphy DJ;Junttila MR;Pouyet L;Karnezis A;Shchors K;Bui DA;Brown-Swigart L;Johnson L;Evan GI
通讯作者：
Evan GI
影响因子：
158.5
作者：
Matthay, KK;Villablanca, JG;Reynolds, CP
通讯作者：
Reynolds, CP
影响因子：
64.8
作者：
Mosse, Yael P.;Laudenslager, Marci;Longo, Luca;Cole, Kristina A.;Wood, Andrew;Attiyeh, Edward F.;Laquaglia, Michael J.;Sennett, Rachel;Lynch, Jill E.;Perri, Patrizia;Laureys, Genevieve;Speleman, Frank;Kim, Cecilia;Hou, Cuiping;Hakonarson, Hakon;Torkamani, Ali;Schork, Nicholas J.;Brodeur, Garrett M.;Tonini, Gian P.;Rappaport, Eric;Devoto, Marcella;Maris, John M.
通讯作者：
Maris, John M.