The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma.
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.
Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
Teeara
T
Berry
William
W
Luther
Namrata
N
Bhatnagar
Yann
Y
Jamin
Evon
E
Poon
Takaomi
T
Sanda
Desheng
D
Pei
Bandana
B
Sharma
Winston R
WR
Vetharoy
Albert
A
Hallsworth
Zai
Z
Ahmad
Karen
K
Barker
Lisa
L
Moreau
Hannah
H
Webber
Wenchao
W
Wang
Qingsong
Q
Liu
Antonio
A
Perez-Atayde
Scott
S
Rodig
Nai-Kong
NK
Cheung
Florence
F
Raynaud
Bengt
B
Hallberg
Simon P
SP
Robinson
Nathanael S
NS
Gray
Andrew D J
AD
Pearson
Suzanne A
SA
Eccles
Louis
L
Chesler
Rani E
RE
George
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction
C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases