Journal
CANCER CELL
Volume 22, Issue 1, Pages 117-130Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.06.001
Keywords
-
Categories
Funding
- US National Institutes of Health [R01 CA148688]
- Sidney Kimmel Translational Scholar Award
- Children's Hospital Boston TRP Pilot Grant
- NIH [CA136851-01A1]
- Catie Hoch Foundation
- Robert Steel Foundation
- SPARKS [09RMH01]
- Neuroblastoma Society [NES003X]
- Medical Research Council (MRC) [NC3R-G1000121/94513]
- ICR
- Cancer Research UK (CRUK) [A14610, C309/A8274, C309/A11566]
- ICR CRUK/EPSRC/MRC
- Department of Health (England) [C1060/A10334]
- CRUK [A10294]
- Wellcome Trust [091763Z/10/Z]
- NHS
- Cancer Research UK [11566] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G1000121/1] Funding Source: researchfish
- Sparks Charity [09RMH01] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available