Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2
Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2
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DOI：
10.1158/1535-7163.mct-19-0505
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发表时间：
2020-02-01
影响因子：
5.7
通讯作者：
Cook, Simon J.
中科院分区：
文献类型：
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作者：
Kidger, Andrew M.;Munck, Joanne M.;Cook, Simon J.
RAS调节的RAF-MEK 1/2-ERK 1/2信号通路在癌症中由于生长因子受体RAS或BRAF的激活突变而经常失调。RAF和MEK 1/2抑制剂均已获得临床批准，各种ERK 1/2抑制剂（ERKi）目前正在进行临床试验。迄今为止，ERKi显示出两种不同的作用机制（MoA）：催化性ERKi仅抑制ERK 1/2催化活性，而双重机制ERKi另外阻止ERK 1/2在其T-E-Y基序处被MEK 1/2活化磷酸化。这些差异可能会在生物活性上产生显著差异，因为T-E-Y磷酸化是ERK 1/2进入核的信号，使它们能够进入许多关键的转录因子靶点。在这里，我们的特点是五个ERKi的MoA和ERK 1/2信号转导，基因表达和抗增殖疗效方面的功能后果进行了研究。我们证明，催化ERKi促进KRAS突变细胞系中p-ERK 1/2的显著核积累。相反，双重机制ERKi利用独特的结合模式来阻断ERK 1/2被MEK 1/2磷酸化，表现出上级效力，并防止ERK 1/2的核积累。因此，与催化性ERKi相比，双机制ERKi表现出更持久的途径抑制和对ERK 1/2依赖性基因表达的增强抑制，从而导致BRAF和RAS突变细胞系的功效增加。
The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date, ERKi display two distinct mechanisms of action (MoA): catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevents the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterized the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signaling, gene expression, and antiproliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS-mutant cell lines. In contrast, dual-mechanism ERKi exploits a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency, and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared with catalytic ERKi, resulting in increased efficacy across BRAF- and RAS-mutant cell lines.