Melanoma articles within Nature

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  • Letter |

    In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.

    • Richard Mark White
    • , Jennifer Cech
    •  & Leonard I. Zon

  • Letter |

    Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes.

    • Craig J. Ceol
    • , Yariv Houvras
    •  & Leonard I. Zon

  • Letter |

    The histone variant mH2A is shown to be expressed at reduced levels in many melanomas. Loss of mH2A promotes tumour growth and metastasis via transcriptional upregulation of CDK8, a known oncogene. This study therefore reveals a new tumour suppression mechanism exerted by epigenetic modifications.

    • Avnish Kapoor
    • , Matthew S. Goldberg
    •  & Emily Bernstein

  • News & Views |

    The promise of an exciting new drug that inhibits the mutant B-RAF protein in skin cancer is marred by the fact that most patients relapse within a year. Fresh data hint at how such resistance emerges. See Letters p.968 & p.973

    • David Solit
    •  & Charles L. Sawyers

  • News |

    Learning how melanoma fights back may yield new therapies.

    • Heidi Ledford

  • Letter |

    Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

    • Cory M. Johannessen
    • , Jesse S. Boehm
    •  & Levi A. Garraway

  • Letter |

    Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

    • Ramin Nazarian
    • , Hubing Shi
    •  & Roger S. Lo

  • Letter |

    PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.

    • Gideon Bollag
    • , Peter Hirth
    •  & Keith Nolop

  • News & Views |

    Tumour cells are non-uniform. The question is whether a distinct subpopulation of the cells drives tumour growth and generates cellular variation. To answer this, the data must be interpreted carefully.

    • Peter Dirks

  • Article |

    When oxygen levels drop in a tissue, the transcription factor hypoxia-inducible factor (HIF) is activated to regulate the cellular response. HIFα levels are increased in most solid tumours and this correlates with a poor prognosis, for unknown reasons. Here it is shown that HIF-1, the worm version of HIFα, protects germ cells from DNA-damage-induced death. It does this remotely, by increasing the production of the TYR-2 protein in distant neurons. Inhibiting a human TYR-2 homologue promotes apoptosis in melanoma cells.

    • Ataman Sendoel
    • , Ines Kohler
    •  & Michael O. Hengartner

  • News |

    Tiny particles carrying short strands of RNA can interfere with protein production in tumours.

    • Janet Fang

  • News & Views |

    Inhibitors of RAF enzymes can suppress or activate the same signalling pathway. The details of how this happens provide a cautionary note for those targeting the pathway for anticancer drug discovery.

    • Karen Cichowski
    •  & Pasi A. Jänne

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