The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma
2012 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 22, no 1, 117-130 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2012. Vol. 22, no 1, 117-130 p.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-57750DOI: 10.1016/j.ccr.2012.06.001ISI: 000306395300013OAI: oai:DiVA.org:umu-57750DiVA: diva2:545367