The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma Academic Article uri icon

Overview

MeSH Major

  • Mutation
  • Neuroblastoma
  • Oncogenes
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases

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.

publication date

  • July 10, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3417812

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2012.06.001

PubMed ID

  • 22789543

Additional Document Info

start page

  • 117

end page

  • 30

volume

  • 22

number

  • 1