Journal
ONCOTARGET
Volume 5, Issue 9, Pages 2688-2702Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1883
Keywords
Neuroblastoma; ALK; neurogenesis; therapeutic target; RET
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Funding
- Institut National du Cancer
- Ligue Nationale contre le Cancer (Equipe labellisee)
- Association Hubert Gouin
- Les Bagouz a Manon, les amis de Claire, la Federation Enfants et Sante et la Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent
- Fondation ARC pour la recherche sur le cancer
- Ecole Polytechnique
- FWO-Flanders (Fund for Scientific Research - Flanders)
- Annenberg foundation
- Wilhelm-Sander-Stiftung
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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 Alk(F1178L) 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 Alk(R1279Q) and MYCN/KI Alk(F1178L) 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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