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Cancer Cell. 2012 Jul 10;22(1):117-30. doi: 10.1016/j.ccr.2012.06.001.

The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma.

Author information

1
Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

Abstract

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 ALK(F1174L) 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.

PMID:
22789543
PMCID:
PMC3417812
DOI:
10.1016/j.ccr.2012.06.001
[Indexed for MEDLINE]
Free PMC Article

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