The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma

被引：241

作者：

Berry, Teeara ^{[1
,2
]}

Luther, William ^{[4
]}

Bhatnagar, Namrata ^{[4
]}

Jamin, Yann ^{[3
]}

Poon, Evon ^{[1
,2
]}

Sanda, Takaomi ^{[4
]}

Pei, Desheng ^{[4
]}

Sharma, Bandana ^{[4
]}

Vetharoy, Winston R. ^{[1
,2
]}

Hallsworth, Albert ^{[1
,2
]}

Ahmad, Zai ^{[1
,2
]}

Barker, Karen ^{[1
,2
]}

Moreau, Lisa ^{[4
]}

Webber, Hannah ^{[1
,2
]}

Wang, Wenchao ^{[4
]}

Liu, Qingsong ^{[5
]}

Perez-Atayde, Antonio ^{[7
]}

Rodig, Scott ^{[6
]}

Cheung, Nai-Kong ^{[8
]}

Raynaud, Florence ^{[1
,2
]}

Hallberg, Bengt ^{[9
]}

Robinson, Simon P. ^{[3
]}

Gray, Nathanael S. ^{[5
]}

Pearson, Andrew D. J. ^{[1
,2
,10
]}

Eccles, Suzanne A. ^{[1
,2
]}

Chesler, Louis ^{[1
,2
,10
]}

George, Rani E. ^{[4
]}

机构：

[1] Inst Canc Res, Div Clin Studies, Surrey SM2 5NG, England

[2] Inst Canc Res, Div Canc Therapeut, Surrey SM2 5NG, England

[3] Inst Canc Res, Div Radiotherapy & Imaging, Surrey SM2 5NG, England

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst & Childrens Hosp Boston, Dept Pediat Hematol & Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst & Biol Chem & Mol Pharmacol, Dept Canc Biol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[7] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

[9] Umea Univ, Dept Mol Biol, Umea, Sweden

[10] Royal Marsden NHS Trust, Children & Young Peoples Unit, Surrey SM2 5PT, England

来源：

CANCER CELL | 2012年 / 22卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会; 英国工程与自然科学研究理事会; 美国国家卫生研究院;

关键词：

ANAPLASTIC LYMPHOMA KINASE; N-MYC; ALK KINASE; C-MYC; ACTIVATING MUTATIONS; EXPRESSION; PHOSPHORYLATION; PROGRESSION; INHIBITION; RESISTANCE;

D O I：

10.1016/j.ccr.2012.06.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The ALK(F1174L) 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 ALK(F1174L) in the neural crest. Compared to ALKF1174L and MYCN alone, co-expression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality. ALK(F1174L)/MYCN tumors exhibited increased MYCN dosage due to ALK(F1174L)-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 ALK(F1174L)/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALK(F1174L) in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.

引用

页码：117 / 130

页数：14

共 26 条

[1] ALKF1174L is a driving oncogene of neuroblastoma in transgenic mice
Schulte, Johannes H.
Heukamp, Lukas
De Preter, Katleen
Thor, Theresa
Speleman, Frank
Schramm, Alexander
Eggert, Angelika
EUROPEAN JOURNAL OF PEDIATRICS, 2012, 171 (09) : 1429 - 1430
[2] ALKF1174L IS A DRIVING ONCOGENE OF NEUROBLASTOMA IN TRANSGENIC MICE
Schulte, Johannes
Heukamp, Lukas
Thor, Theresa
Kumps, Candy
De Preter, Katleen
De Wilde, Bram
Vandesompele, Jo
Speleman, Frank
Schramm, Alexander
Eggert, Angelika
PEDIATRIC BLOOD & CANCER, 2012, 59 (06) : 989 - 989
[3] MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells
Schulte, J. H.
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De Preter, K.
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Heukamp, L.
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Speleman, F.
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ONCOGENE, 2013, 32 (08) : 1059 - 1065
[4] MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells
J H Schulte
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J Maurer
K De Preter
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J Molenaar
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A Künkele
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H Schorle
A Eggert
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Oncogene, 2013, 32 : 1059 - 1065
[5] Oncogenic ALKF1174L drives tumorigenesis in cutaneous squamous cell carcinoma
Gualandi, Marco
Iorio, Maria
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Serra-Roma, Andre
Gasparre, Giuseppe
Schulte, Johannes H.
Hohl, Daniel
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LIFE SCIENCE ALLIANCE, 2020, 3 (06)
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Zhang, Libo
Wu, Bing
Baruchel, Sylvain
TRANSLATIONAL ONCOLOGY, 2017, 10 (04): : 604 - 611
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Jamin, Yann
Glass, Laura
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Koh, Dow-Mu
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Chesler, Louis
Robinson, Simon P.
PLOS ONE, 2014, 9 (03):
[8] Intrinsic susceptibility magnetic resonance imaging identifies tumors with ALKF1174L mutation in transgenic murine models of high-risk neuroblastoma.
Jamin, Yann
Glass, Laura
Hallsworth, Albert
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Koh, Dow-Mu
Pearson, Andrew D. J.
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CANCER RESEARCH, 2013, 73 (08)
[9] The ALK-F1174L mutation accelerates MYCN-driven tumorigenesis in a murine transgenic neuroblastoma model
George, Rani E.
Luther, William
Ahmad, Zahida
Cullis, Elizabeth R.
Webber, Hannah
Rodig, Scott
Pearson, Andrew D. J.
Chesler, Louis
CANCER RESEARCH, 2011, 71
[10] ALK inhibitor resistance in ALKF1174L-driven neuroblastoma is associated with AXL activation and induction of EMT
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Bhatnagar, N.
Sharma, B.
Luther, W.
Moore, N. F.
Cheung, K.
Gray, N. S.
George, R. E.
ONCOGENE, 2016, 35 (28) : 3681 - 3691

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