Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients

Lorena Passoni, Luca Longo, Paola Collini, Addolorata Maria Luce Coluccia, Fabio Bozzi, Marta Podda, Andrea Gregorio, Claudio Gambini, Alberto Garaventa, Vito Pistoia, Federica Del Grosso, Gian Paolo Tonini, Mangeng Cheng, Carlo Gambacorti-Passerini, Andrea Anichini, Franca Fossati-Bellani, Massimo Di Nicola, Roberto Luksch

Research output: Contribution to journalArticle

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified as a major oncogene associated with familial and sporadic neuroblastomas (NBL). Yet, a direct correlation between endogenous expression level of the ALK protein, oncogenic potential, and clinical outcome has not been established. We investigated ALK genetic mutations, protein expression/phosphorylation, and functional inhibition both in NBL-derived cell lines and in 34 localized and 48 advanced/metastatic NBL patients. ALK constitutive phosphorylation/activation was observed in high-ALK expressing cells, harboring either a mutated or a wild-type receptor. No activation was found in cell lines with low expression of wild-type ALK. After 72 hours of treatments, small molecule ALK inhibitor CEP-14083 (60 nmol/L) induced growth arrest and cell death in NBL cells overexpressing wild-type (viability: ALK high 12.8%, ALKlow 73%, P = 0.0035; cell death: ALK high 56.4%, ALKlow 16.2%, P = 0.0001) or mutated ALK. ALK protein expression was significantly up-regulated in advanced/metastatic compared with localized NBLs (ALK overexpressing patients: stage 1-2, 23.5%; stage 3-4, 77%; P <0.0001). Interestingly, protein levels did not always correlate with ALK genetic alterations and/or mRNA abundance. Both mutated and wild-type ALK receptor can exert oncogenic activity in NBL cells. However, wild-type ALK receptor requires a critical threshold of expression to achieve oncogenic activation. Overexpression of either mutated or wild-type ALK defines poor prognosis patients. Alternative mechanisms other than direct mutations and/or gene amplification regulate the ALK level of expression in NBL cells. Wild-type ALK is a potential therapeutic target for advanced/metastatic NBLs.

Original languageEnglish
Pages (from-to)7338-7346
Number of pages9
JournalCancer Research
Volume69
Issue number18
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Passoni, L., Longo, L., Collini, P., Coluccia, A. M. L., Bozzi, F., Podda, M., Gregorio, A., Gambini, C., Garaventa, A., Pistoia, V., Del Grosso, F., Tonini, G. P., Cheng, M., Gambacorti-Passerini, C., Anichini, A., Fossati-Bellani, F., Di Nicola, M., & Luksch, R. (2009). Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Research, 69(18), 7338-7346. https://doi.org/10.1158/0008-5472.CAN-08-4419