Author/Authors :
Berry، نويسنده , , Teeara and Luther، نويسنده , , William and Bhatnagar، نويسنده , , Namrata and Jamin، نويسنده , , Yann and Poon، نويسنده , , Evon and Sanda، نويسنده , , Takaomi and Pei، نويسنده , , Desheng and Sharma، نويسنده , , Bandana and Vetharoy، نويسنده , , Winston R. and Hallsworth، نويسنده , , Albert and Ahmad، نويسنده , , Zai and Barker، نويسنده , , Karen and Moreau، نويسنده , , Lisa and Webber، نويسنده , , Hannah and Wang، نويسنده , , Wenchao and Liu، نويسنده , , Qingsong and Perez-Atayde، نويسنده , , Antonio and Rodig، نويسنده , , Scott and Cheung، نويسنده , , Nai-Kong and Raynaud، نويسنده , , Florence and Hallberg، نويسنده , , Bengt and Robinson، نويسنده , , Simon P. and Gray، نويسنده , , Nathanael S. and Pearson، نويسنده , , Andrew D.J. and Eccles، نويسنده , , Suzanne A. and Chesler، نويسنده , , Louis and George، نويسنده , , Rani E.، نويسنده ,
Abstract :
Summary
KF1174L 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 ALKF1174L 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. ALKF1174L/MYCN tumors exhibited increased MYCN dosage due to ALKF1174L-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 ALKF1174L/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALKF1174L in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.
