ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer
ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer
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DOI：
10.1016/j.celrep.2014.05.032
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发表时间：
2014-06-26
期刊：
影响因子：
8.8
通讯作者：
Johnston, Patrick G.
中科院分区：
文献类型：
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作者：
Van Schaeybroeck, Sandra;Kalimutho, Murugan;Johnston, Patrick G.
目前尚无针对晚期KRAS突变（KRASMT）结直肠癌（CRC）的获批靶向治疗。使用一种独特的系统生物学方法，我们确定JAK 1/2依赖性激活STAT 3作为耐药的关键介质在体外和体内的KRASMT CRC的MEK抑制剂。进一步的分析确定了在KRASMT CRC模型中用MEK抑制剂治疗后c-MET活性的急性增加，这被证明促进JAK 1/2-STAT 3介导的抗性。此外，发现MEK抑制后c-MET的活化是由于ERK依赖性金属蛋白酶ADAM 17的抑制，其通常通过促进其内源性拮抗剂可溶性“诱饵”MET的脱落来抑制c-MET信号传导。最重要的是，在体外和体内KRASMT模型中，c-MET或JAK 1/2抑制剂对该耐药途径的药理学阻断协同增加了MEK抑制剂诱导的细胞凋亡和生长抑制，为KRASMT CRC患者中这些组合的临床评估提供了明确的依据。
There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance to MEK inhibitors in KRASMT CRC in vitro and in vivo. Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found to be due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergistically increased MEK-inhibitor-induced apoptosis and growth inhibition in vitro and in vivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.