[PDF][PDF] Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma

M Brockmann, E Poon, T Berry, A Carstensen… - Cancer cell, 2013 - cell.com
M Brockmann, E Poon, T Berry, A Carstensen, HE Deubzer, L Rycak, Y Jamin, K Thway…
Cancer cell, 2013cell.com
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors,
including neuroblastoma. No small molecules that target N-Myc, the protein encoded by
MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which
protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not
require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors,
MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of …
Summary
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
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