Targeting the mitochondria for the therapy of MYCN-amplified neuroblastoma

Melinda Halasz

Neuroblastoma (NB) is one of the deadliest childhood cancers, most commonly originating from the adrenal medulla. Despite extensive research, the five-year survival rate for children with high-risk NB is still below 50%; thus, better therapies are desperately needed. Amplification of the MYCN oncogene drives half of high-risk cases. Therefore, our aim was to identify therapeutically targetable nodes that function as critical effectors of MYCN. We mapped the MYCN-interactome across a panel of NB cell lines and tumour samples; and found that MYCN interacts with mitochondrial proteins. We found that certain mitochondrial genes are downregulated in patients with MYCN-amplified NB, and correlate with poor patient survival. In addition, high-throughput drug screening revealed that a complex I inhibitor suppresses the proliferation of MYCN-amplified NB cells. We showed that this inhibitor i) downregulates MYCN expression, and in turn, modulates mitochondrial gene expression dependent on MYCN status; ii) increases mitochondrial oxidative stress; iii) induces differentiation; iv) reduces transformation of MYCN-amplified NB cells; and v) reduces tumour size in zebrafish models of MYCN-driven neuroblastoma.

In summary, we showed that a complex I inhibitor affects mitochondrial functions dependent on MYCN status, induces mitochondrial superoxide-mediated apoptosis and differentiation of MYCN-amplified NB cells; and inhibits NB growth both in vitro and in vivo. Therefore, targeting complex I of the mitochondria might serve as a potential new approach to treat MYCN-amplified NB.