MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models.
MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models.
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DOI：
10.1038/s41422-018-0044-4
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发表时间：
2018-07
期刊：
影响因子：
44.1
通讯作者：
Bernards R
中科院分区：
文献类型：
--
作者：
Xue Z;Vis DJ;Bruna A;Sustic T;van Wageningen S;Batra AS;Rueda OM;Bosdriesz E;Caldas C;Wessels LFA;Bernards R
丝裂原活化蛋白激酶(MAPK)通路的激活在癌症中很常见。药物开发的努力一直集中在这一途径中的激酶上，最明显的是RAF和MEK。我们在这里表明，MEK抑制通过抑制DUSP4激活JNK-Jun信号，导致HER受体酪氨酸激酶的激活。这会在药物存在的情况下刺激MAPK通路，从而钝化MEK抑制的效果。失去MAP3K1或MAP2K4的癌症患者无法激活JNK-jun。因此，MAP3K1或MAP2K4的功能缺失突变通过在MEK抑制时使JNK-Jun介导的反馈环失效而使其对MEK抑制具有敏感性。在168例患者来源的异种移植(PDX)肿瘤中，MAP3K1和MAP2K4突变状态是对MEK抑制反应的强烈预测因素。我们的发现表明，乳腺癌、前列腺癌和结肠癌中常见的MAP3K1或MAP2K4突变的癌症可能对MEK抑制剂有反应。我们的发现还表明，尽管MAP3K1和MAP2K4是由肿瘤抑制基因编码的，但它们与MEK抑制剂联合使用是潜在的药物靶点。
Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.
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影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
64.5
作者：
Burgess MR;Hwang E;Mroue R;Bielski CM;Wandler AM;Huang BJ;Firestone AJ;Young A;Lacap JA;Crocker L;Asthana S;Davis EM;Xu J;Akagi K;Le Beau MM;Li Q;Haley B;Stokoe D;Sampath D;Taylor BS;Evangelista M;Shannon K
通讯作者：
Shannon K
影响因子：
5.3
作者：
Mialon, A;Sankinen, M;Westermarck, J
通讯作者：
Westermarck, J
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network