Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.
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.
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Anna A
AA
Marusiak
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Zoe C
ZC
Edwards
1] Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA [2].
Willy
W
Hugo
1] Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK [2].
Eleanor W
EW
Trotter
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Maria R
MR
Girotti
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Natalie L
NL
Stephenson
Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA.
Xiangju
X
Kong
Oncogenomics Research Group, QIMR Berghofer Medical Research Institute, Herston, Brisbane QLD 4006, Australia.
Michael G
MG
Gartside
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Shameem
S
Fawdar
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Andrew
A
Hudson
Cell Regulation Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Wolfgang
W
Breitwieser
Oncogenomics Research Group, QIMR Berghofer Medical Research Institute, Herston, Brisbane QLD 4006, Australia.
Nicholas K
NK
Hayward
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Richard
R
Marais
Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA.
Roger S
RS
Lo
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
John
J
Brognard
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000077484:Vemurafenib
D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases