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Nat Commun. 2014 May 22;5:3901. doi: 10.1038/ncomms4901.

Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.

Author information

1
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
2
1] Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA [2].
3
1] Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK [2].
4
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
5
Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA.
6
Oncogenomics Research Group, QIMR Berghofer Medical Research Institute, Herston, Brisbane QLD 4006, Australia.
7
Cell Regulation Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.

Abstract

RAF inhibitor therapy yields significant reductions in tumour burden in the majority of V600E-positive melanoma patients; however, resistance occurs within 2-18 months. Here we demonstrate that the mixed lineage kinases (MLK1-4) are MEK kinases that reactivate the MEK/ERK pathway in the presence of RAF inhibitors. Expression of MLK1-4 mediates resistance to RAF inhibitors and promotes survival in V600E-positive melanoma cell lines. Furthermore, we observe upregulation of the MLKs in 9 of 21 melanoma patients with acquired drug resistance. Consistent with this observation, MLKs promote resistance to RAF inhibitors in mouse models and contribute to acquired resistance in a cell line model. Lastly, we observe that a majority of MLK1 mutations identified in patients are gain-of-function mutations. In summary, our data demonstrate a role for MLKs as direct activators of the MEK/ERK pathway with implications for melanomagenesis and resistance to RAF inhibitors.

PMID:
24849047
PMCID:
PMC4046110
DOI:
10.1038/ncomms4901
[Indexed for MEDLINE]
Free PMC Article

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