Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.
Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.
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DOI：
10.1038/ncomms4901
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发表时间：
2014-05-22
影响因子：
16.6
通讯作者：
Brognard, John
中科院分区：
文献类型：
--
作者：
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
RAF抑制剂治疗在大多数V600 E阳性黑色素瘤患者中产生肿瘤负荷的显著降低;然而，耐药发生在2-18个月内。在这里，我们证明了混合谱系激酶（MLK 1 -4）是MEK激酶，在RAF抑制剂的存在下重新激活MEK/ERK通路。MLK 1 -4的表达介导对RAF抑制剂的抗性并促进V600 E阳性黑素瘤细胞系的存活。此外，我们观察到MLKs在21例获得性耐药的黑色素瘤患者中的9例中上调。与该观察结果一致，MLK在小鼠模型中促进对RAF抑制剂的抗性，并在细胞系模型中促成获得性抗性。最后，我们观察到在患者中鉴定的大多数MLK 1突变是功能获得性突变。总之，我们的数据证明了MLKs作为MEK/ERK通路的直接激活剂的作用，并暗示了黑色素瘤的发生和对RAF抑制剂的耐药性。 B-Raf在许多黑色素瘤中发生突变，但用靶向突变蛋白的小分子治疗这种疾病通常会导致肿瘤耐药性。在这里，作者表明，混合谱系激酶（MLK 1 -4）可以在抑制剂存在下重新激活B-Raf信号通路，导致耐药性。
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. B-Raf is mutated in many melanomas but treatment of the disease with small molecules targeting the mutant protein often results in tumour resistance. Here, the authors show that mixed lineage kinases (MLK1-4) can reactivate the B-Raf signalling pathway in the presence of inhibitors, resulting in drug resistance.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
30.8
作者：
Stark, Mitchell S.;Woods, Susan L.;Gartside, Michael G.;Bonazzi, Vanessa F.;Dutton-Regester, Ken;Aoude, Lauren G.;Chow, Donald;Sereduk, Chris;Niemi, Natalie M.;Tang, Nanyun;Ellis, Jonathan J.;Reid, Jeffrey;Zismann, Victoria;Tyagi, Sonika;Muzny, Donna;Newsham, Irene;Wu, YuanQing;Palmer, Jane M.;Pollak, Thomas;Youngkin, David;Brooks, Bradford R.;Lanagan, Catherine;Schmidt, Christopher W.;Kobe, Bostjan;MacKeigan, Jeffrey P.;Yin, Hongwei;Brown, Kevin M.;Gibbs, Richard;Trent, Jeffrey;Hayward, Nicholas K.
通讯作者：
Hayward, Nicholas K.
影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
4.3
作者：
Le, Kaitlyn;Blomain, Erik S.;Aplin, Andrew E.
通讯作者：
Aplin, Andrew E.
影响因子：
28.2
作者：
Shi H;Hugo W;Kong X;Hong A;Koya RC;Moriceau G;Chodon T;Guo R;Johnson DB;Dahlman KB;Kelley MC;Kefford RF;Chmielowski B;Glaspy JA;Sosman JA;van Baren N;Long GV;Ribas A;Lo RS
通讯作者：
Lo RS