The ALK(F1174L) Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2012 Jul 14

PMID 22789543

Citations 168

Authors

Teeara Berry

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

Affiliations

Soon will be listed here.

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.

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