Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma

// Alex Cazes 1,2 , Lucille Lopez-Delisle 1,2 , Konstantina Tsarovina 3 , Cecile Pierre-Eugene 1,2 , Katleen De Preter 4 , Michel Peuchmaur 5,6 , Andre Nicolas 7 , Claire Provost 8 , Caroline Louis-Brennetot 1,2 , Romain Daveau 1,2 , Candy Kumps 4 , Ilaria Cascone 9 , Gudrun Schleiermacher 1,2,10 , Aurelie Prignon 8 , Frank Speleman 4 , Hermann Rohrer 3 , Olivier Delattre 1,2 and Isabelle Janoueix-Lerosey 1,2 1 Inserm U830, 26 rue d’Ulm, 75005 Paris, France. 2 Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75005 Paris, France. 3 Research Group Developmental Neurobiology, Max Planck Institute for Brain Research, Max-von-Laue-Str. 4, 60438 Frankfurt/M, Germany. 4 Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. 5 Departement of Pathology, AP-HP, Hopital Universitaire Robert Debre, 48 boulevard Serurier, 75019 Paris, France. 6 Universite Diderot Paris 7, Paris Sorbonne Cite, Paris, France. 7 Platform of Experimental Pathology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. 8 LIMP (Laboratoire d’Imagerie Moleculaire Positonique), Hopital Tenon, 4 rue de la Chine, 75020 Paris, France. 9 Laboratoire CRRET, EAC CNRS 7149, Universite Paris 12-Val de Marne, 61, avenue du General de Gaulle, 94010 Creteil, France. 10 Institut Curie, Departement de Pediatrie, 26 rue d’Ulm, 75005 Paris, France. Correspondence: Isabelle Janoueix-Lerosey, email: // Keywords : Neuroblastoma, ALK, neurogenesis, therapeutic target, RET Received : March 24, 2014 Accepted : April 01, 2014 Published : April 02, 2014 Abstract 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.