TY - JOUR
T1 - Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients
AU - Passoni, Lorena
AU - Longo, Luca
AU - Collini, Paola
AU - Coluccia, Addolorata Maria Luce
AU - Bozzi, Fabio
AU - Podda, Marta
AU - Gregorio, Andrea
AU - Gambini, Claudio
AU - Garaventa, Alberto
AU - Pistoia, Vito
AU - Del Grosso, Federica
AU - Tonini, Gian Paolo
AU - Cheng, Mangeng
AU - Gambacorti-Passerini, Carlo
AU - Anichini, Andrea
AU - Fossati-Bellani, Franca
AU - Di Nicola, Massimo
AU - Luksch, Roberto
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-08-4419
DO - 10.1158/0008-5472.CAN-08-4419
M3 - Article
C2 - 19723661
AN - SCOPUS:70349733112
VL - 69
SP - 7338
EP - 7346
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 18
ER -