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

[21] KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma
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[22] KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma
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[23] Oncogenic activity of human MYD88L265P mutation in mature B-cells in vivo
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[24] Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L
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[25] Whole Genome Sequencing Reveals a Widely Expressed Mutation (MYD88 L265P) with Oncogenic Activity in Waldenstrom's Macroglobulinemia
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[26] Wild-type ALK and both ALK-R1275Q and ALK-F1174L activating mutations display a strong oncogenic activity in vivo in murine neural crest progenitor cells via cooperation with c-myc
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