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

  • Author(s): Marusiak, Anna A
  • Edwards, Zoe C
  • Hugo, Willy
  • Trotter, Eleanor W
  • Girotti, Maria R
  • Stephenson, Natalie L
  • Kong, Xiangju
  • Gartside, Michael G
  • Fawdar, Shameem
  • Hudson, Andrew
  • Breitwieser, Wolfgang
  • Hayward, Nicholas K
  • Marais, Richard
  • Lo, Roger S
  • Brognard, John
  • et al.
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.

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