| Literature DB >> 22789543 |
Teeara Berry1, William Luther, Namrata Bhatnagar, Yann Jamin, Evon Poon, Takaomi Sanda, Desheng Pei, Bandana Sharma, Winston R Vetharoy, Albert Hallsworth, Zai Ahmad, Karen Barker, Lisa Moreau, Hannah Webber, Wenchao Wang, Qingsong Liu, Antonio Perez-Atayde, Scott Rodig, Nai-Kong Cheung, Florence Raynaud, Bengt Hallberg, Simon P Robinson, Nathanael S Gray, Andrew D J Pearson, Suzanne A Eccles, Louis Chesler, Rani E George.
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.Entities:
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Year: 2012 PMID： 22789543 PMCID： PMC3417812 DOI： 10.1016/j.ccr.2012.06.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743