Abstract
High‐risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high‐risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8–10% of primary NB patients are ALK‐positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p‐gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v‐sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI‐sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p‐gain, may benefit from ALK TKI‐based therapeutic intervention.
Highlights
High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer
These Alkal2;ThMYCN-driven NBs are similar to anaplastic lymphoma kinase (ALK) gain-of-function-driven NB as assessed by RNA-Seq and respond to ALK tyrosine kinase inhibitors (TKIs) treatment. These results indicate that aberrant regulation of the ALKAL2 ligand can drive NB, and most importantly suggest that a proportion of “ALK mutation-negative” NB patients may benefit from ALK TKI-based therapeutic intervention
To verify whether ALK signalling was induced by ALKAL2, we first stimulated NB1 and IMR-32 cells with ALKAL2 for 30 min and 24 h, and monitored ALK activation by immunoblotting against pY1278-ALK and downstream signalling with pAKT, pERK and pS6 (Appendix Fig S1)
Summary
High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of highrisk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p-gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. We tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p-gain, may benefit from ALK TKI-based therapeutic intervention
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