Editors' ChoiceCancer

Drugging the Undruggable

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Science Translational Medicine  07 Aug 2013:
Vol. 5, Issue 197, pp. 197ec131
DOI: 10.1126/scitranslmed.3007131

We know what drives oncogenesis in many pediatric cancers, but designing drugs that target these pathways has been difficult. In pediatric neuroblastoma, for example, amplification and subsequent deregulation of the MYCN oncogene characterizes a highly aggressive and expansive subset of cancers. MYCN drives neuroblastoma development and progression, as shown in cell cultures and mouse models in which researchers have elucidated the downstream signaling networks that regulate oncogenic function. One downstream mediator is Aurora-A kinase, which binds to and stabilizes N-Myc, preventing its degradation. Although no clinically available small molecules directly target N-Myc, two Aurora-A allosteric inhibitors can distort Aurora-A’s conformation without inhibiting its kinase activity and so prevent its association with N-Myc. With this in mind, Brockmann and colleagues tested the effects of these Aurora-A inhibitors on N-Myc–driven neuroblastoma cell lines in order to define the inhibitors’ therapeutic potential.

Using a variety of assays in MYCN-amplified neuroblastomas, Brockmann et al. characterized the effects of MLN8054 and the clinical lead compound MLN8237 on Aurora-A/N-Myc complex formation. In their hands, both inhibitors decreased protein expression of N-Myc by specifically disrupting the Aurora-A/N-Myc complex. This intervention resulted in F-box/WD repeat–containing protein 7 (SCFFBW7)–mediated degradation of N-Myc and reduced cell viability.

The drugs were effective in animals also. In tyrosine hydroxylase (TH)–MYCN mouse models of neuroblastoma, treatment with MLN8054 prolonged survival and caused striking tumor regression via disassociation of the Aurora-A/N-Myc complex. Subsequent degradation of N-Myc inhibited the transcription of prognostically significant N-Myc target genes. Overall, these studies demonstrate that MLN8054 and MLN8237 disrupt the Aurora-A/N-Myc complex in neuroblastomas, promoting N-Myc degradation and prolonging survival. The results indicate that Aurora-A is a potential therapeutic target in N-Myc–driven neuroblastomas, presenting an opportunity to further develop targeted therapies for childhood neuroblastomas.

M. Brockmann et al., Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-Myc in childhood neuroblastoma. Cancer Cell 24, 7589 (2013). [Abstract]

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