Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation.
Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation.
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DOI：
10.1080/15384101.2015.1120915
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Cook SJ
中科院分区：
文献类型：
--
作者：
Lochhead PA;Clark J;Wang LZ;Gilmour L;Squires M;Gilley R;Foxton C;Newell DR;Wedge SR;Cook SJ
已经提出由MAPK 7编码的ERK 5在细胞增殖中发挥作用，因此作为癌症治疗靶点引起了人们的兴趣。虽然致癌RAS或BRAF引起MEK 1/2-ERK 1/2通路的持续激活，但ERK 5直接被MEK 5激活。已经提出RAS和RAF蛋白也可以促进ERK 5活化。在此，我们研究了RAS-RAF-MEK-ERK和ERK 5信号之间的相互作用，并在2种疾病相关细胞模型中研究了ERK 5在肿瘤细胞增殖中的作用。我们证明，虽然诱导型CRAF（CRAF：ER*）可以激活成纤维细胞中的ERK 5，反应是延迟的，反映了前馈信号。此外，致癌KRAS和BRAF不激活上皮细胞中的ERK 5。虽然KRAS和BRAF不直接偶联到MEK 5-ERK 5，但ERK 5信号传导可能仍然允许增殖。然而，选择性MEK 5抑制剂BIX 02189或ERK 5 siRNA都不能抑制携带KRASG 12 C/G13 D或BRAFV 600 E的结直肠癌细胞的增殖。此外，当BIX 02189与MEK 1/2抑制剂Selumetinib（AZD 6244）组合时，没有观察到累加或协同效应，表明ERK 5既不是增殖所需的，也不是对MEK 1/2抑制剂的先天抗性的驱动因素。最后，甚至具有MAPK 7扩增的癌细胞也对BIX 02189和ERK 5 siRNA具有抗性，表明ERK 5扩增不会使细胞增殖对ERK 5成瘾。因此，ERK 5信号传导不太可能在KRAS或BRAF下游的肿瘤细胞增殖中或在具有ERK 5扩增的肿瘤细胞中发挥作用。这些结果对ERK 5作为抗癌药物靶点的作用具有重要意义。
ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling. Additionally, oncogenic KRAS and BRAF do not activate ERK5 in epithelial cells. Although KRAS and BRAF do not couple directly to MEK5-ERK5, ERK5 signaling might still be permissive for proliferation. However, neither the selective MEK5 inhibitor BIX02189 or ERK5 siRNA inhibited proliferation of colorectal cancer cells harbouring KRASG12C/G13D or BRAFV600E. Furthermore, there was no additive or synergistic effect observed when BIX02189 was combined with the MEK1/2 inhibitor Selumetinib (AZD6244), suggesting that ERK5 was neither required for proliferation nor a driver of innate resistance to MEK1/2 inhibitors. Finally, even cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA, showing that ERK5 amplification does not confer addiction to ERK5 for cell proliferation. Thus ERK5 signaling is unlikely to play a role in tumor cell proliferation downstream of KRAS or BRAF or in tumor cells with ERK5 amplification. These results have important implications for the role of ERK5 as an anti-cancer drug target.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
6.7
作者：
Deng, Xianming;Elkins, Jonathan M.;Zhang, Jinwei;Yang, Qingkai;Erazo, Tatiana;Gomez, Nestor;Choi, Hwan Geun;Wang, Jinhua;Dzamko, Nicolas;Lee, Jiing-Dwan;Sim, Taebo;Kim, NamDoo;Alessi, Dario R.;Lizcano, Jose M.;Knapp, Stefan;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
5.7
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
4.8
作者：
Gilley, Rebecca;March, H. Nikki;Cook, Simon J.
通讯作者：
Cook, Simon J.
影响因子：
4.8
作者：
Abe, J;Takahashi, M;Berk, BC
通讯作者：
Berk, BC