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Ref Type Journal Article
PMID (24811913)
Authors Cazes A, Lopez-Delisle L, Tsarovina K, Pierre-Eugène C, De Preter K, Peuchmaur M, Nicolas A, Provost C, Louis-Brennetot C, Daveau R, Kumps C, Cascone I, Schleiermacher G, Prignon A, Speleman F, Rohrer H, Delattre O, Janoueix-Lerosey I
Title Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma.
Journal Oncotarget
Vol 5
Issue 9
Date 2014 May 15
URL
Abstract Text Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK R1275Q neuroblastoma sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK R1275Q (corresponds to R1279Q in mouse) and subsequent upregulation of Ret (PMID: 24811913). 24811913
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical Actionable In a preclinical study, Xalkori (crizotinib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK R1275Q (corresponds to R1279Q in mouse) and subsequent upregulation of Ret (PMID: 24811913). 24811913
ALK F1174L neuroblastoma sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK F1174L (corresponds to F1178L in mouse) and subsequent upregulation of Ret (PMID: 24811913). 24811913