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Targeting MYCN and ALK in resistant and relapsing neuroblastoma
Elizabeth R Tucker1, Evon Poon1, Louis Chesler1
1Division of Clinical Studies, The Institute of Cancer Research, Sutton, SM2 5NG, UK.
Abstract:
Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.
Insights
High-risk neuroblastoma involves MYCN amplification and ALK mutations, leading to poor survival. New therapies targeting MYCN transcription and ALK are under investigation to improve outcomes for relapsed patients.
Area of Science:
- Pediatric Oncology
- Cancer Genomics
- Molecular Therapeutics
Background:
- Neuroblastoma is the most common pediatric solid tumor, with high-risk cases frequently experiencing fatal relapse.
- Relapsed high-risk neuroblastoma is characterized by MYCN oncogene amplification and anaplastic lymphoma kinase (ALK) mutations.
- Current treatment options for relapsed neuroblastoma are limited, with poor survival rates.
Purpose of the Study:
- To review international efforts in identifying therapeutically targetable mechanisms in neuroblastoma.
- To explore the mechanistic link between ALK and MYCN in neuroblastoma pathogenesis.
- To discuss emerging therapeutic strategies targeting MYCN and ALK.
Main Methods:
- Review of existing literature on neuroblastoma genetics and therapeutic resistance.
- Analysis of the functional interaction between ALK and MYCN.
- Examination of ongoing clinical trials for novel neuroblastoma treatments.
Main Results:
- High-level MYCN amplification and ALK kinase domain mutations are key genomic alterations in relapsed neuroblastoma.
- ALK signaling upregulates MYCN transcription, presenting a therapeutic vulnerability.
- Existing ALK inhibitors show limited efficacy due to de novo resistance in neuroblastoma patients.
Conclusions:
- Targeting the ALK-MYCN axis is a promising strategy for high-risk neuroblastoma.
- Development of MYCN transcriptional inhibitors and effective ALK inhibitors is crucial.
- Clinical trials are exploring novel small-molecule inhibitors for neuroblastoma treatment.
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