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Abstract
Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related ‘bypass’ mechanisms and concomitant oncogenic pathways.
Highlights
IntroductionNeuroblastoma (NB) is the most common solid extracranial malignancy in children, representing
Neuroblastoma (NB) is the most common solid extracranial malignancy in children, representing7–10% of paediatric cancers and accounting for 15% of all paediatric cancer deaths [1,2,3]
Other oncogenic mechanisms leading to aberrant Anaplastic Lymphoma Kinase (ALK) activity include point mutations in the kinase domain and gene amplification, as observed in neuroblastoma and NSCLC amongst other cancers (Figure 1b) [11,12,25,43,44]
Summary
Neuroblastoma (NB) is the most common solid extracranial malignancy in children, representing. 7–10% of paediatric cancers and accounting for 15% of all paediatric cancer deaths [1,2,3]. The median age of diagnosis is around 2 years, with 90% of cases diagnosed by 5 years of age. Often termed a ‘clinical enigma’, NB is a complex disease due to its heterogeneous biology and clinical behaviour, ranging from spontaneous regression to treatment-resistant progression, metastasis and death [4]. Whereas low- and intermediate-risk disease is highly curable, with five-year survival exceeding 90%, high-risk disease, which accounts for around half of all cases at diagnosis, is associated with frequent relapse and a markedly poorer five-year survival of.
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