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

Anna A. Marusiak, Zoe C. Edwards, Willy Hugo, Eleanor W. Trotter, Maria R. Girotti, Natalie L. Stephenson, Xiangju Kong, Michael G. Gartside, Shameem Fawdar, Andrew Hudson, Wolfgang Breitwieser, Nicholas K. Hayward, Richard Marais, Roger S. Lo and John Brognard ()
Additional contact information
Anna A. Marusiak: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Zoe C. Edwards: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Willy Hugo: Jonsson Comprehensive Cancer Center and the University of California
Eleanor W. Trotter: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Maria R. Girotti: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester
Natalie L. Stephenson: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Xiangju Kong: Jonsson Comprehensive Cancer Center and the University of California
Michael G. Gartside: Oncogenomics Research Group, QIMR Berghofer Medical Research Institute
Shameem Fawdar: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Andrew Hudson: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester
Wolfgang Breitwieser: Cell Regulation Group, Cancer Research UK Manchester Institute, The University of Manchester
Nicholas K. Hayward: Oncogenomics Research Group, QIMR Berghofer Medical Research Institute
Richard Marais: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester
Roger S. Lo: Jonsson Comprehensive Cancer Center and the University of California
John Brognard: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4901

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