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
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
1] Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center and the University of California, Los Angeles, California 90095-1750, USA [2].
Nat Commun. 2014 May 22;5:3901. doi: 10.1038/ncomms4901.
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.
RAF抑制剂疗法可使大多数V600E阳性黑色素瘤患者的肿瘤负担显著降低；然而，耐药性会在2至18个月内出现。在此，我们证明混合谱系激酶（MLK1 - 4）是MEK激酶，在存在RAF抑制剂的情况下可重新激活MEK/ERK通路。MLK1 - 4的表达介导对RAF抑制剂的耐药性，并促进V600E阳性黑色素瘤细胞系的存活。此外，我们在21例获得性耐药的黑色素瘤患者中的9例中观察到MLK的上调。与这一观察结果一致，MLK在小鼠模型中促进对RAF抑制剂的耐药性，并在细胞系模型中导致获得性耐药。最后，我们观察到在患者中鉴定出的大多数MLK1突变是功能获得性突变。总之，我们的数据证明MLK作为MEK/ERK通路的直接激活剂在黑色素瘤发生和对RAF抑制剂耐药性方面具有重要作用。
