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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The PP242 Mammalian Target of Rapamycin (mTOR) Inhibitor Activates Extracellular Signal-regulated Kinase (ERK) in Multiple Myeloma Cells via a Target of Rapamycin Complex 1 (TORC1)/ Eukaryotic Translation Initiation Factor 4E (eIF-4E)/RAF Pathway and Activation Is a Mechanism of Resistance
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The PP242 Mammalian Target of Rapamycin (mTOR) Inhibitor Activates Extracellular Signal-regulated Kinase (ERK) in Multiple Myeloma Cells via a Target of Rapamycin Complex 1 (TORC1)/ Eukaryotic Translation Initiation Factor 4E (eIF-4E)/RAF Pathway and Activation Is a Mechanism of Resistance

机译：雷帕霉素（mTOR）抑制剂的PP242哺乳动物靶标通过雷帕霉素复合物1（TORC1）/真核翻译起始因子4E（eIF-4E）/ RAF途径和活化途径激活多发性骨髓瘤细胞中的细胞外信号调节激酶（ERK）。抵抗机制

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Activation of PI3-K-AKT and ERK pathways is a complication of mTOR inhibitor therapy. Newer mTOR inhibitors (like pp242) can overcome feedback activation of AKT in multiple myeloma (MM) cells. We, thus, studied if feedback activation of ERK is still a complication of therapy with such drugs in this tumor model. PP242 induced ERK activation in MM cell lines as well as primary cells. Surprisingly, equimolar concentrations of rapamycin were relatively ineffective at ERK activation. Activation was not correlated with P70S6kinase inhibition nor was it prevented by PI3-kinase inhibition. ERK activation was prevented by MEK inhibitors and was associated with concurrent stimulation of RAF kinase activity but not RAS activation. RAF activation correlated with decreased phosphorylation of RAF at Ser-289, Ser-296, and Ser-301 inhibitory residues. Knockdown studies confirmed TORC1 inhibition was the key proximal event that resulted in ERK activation. Furthermore, ectopic expression of eIF-4E blunted pp242-induced ERK phosphorylation. Since pp242 was more potent than rapamycin in causing sequestering of eIF-4E, a TORC1/4E-BP1/eIF-4E-mediated mechanism of ERK activation could explain the greater effectiveness of pp242. Use of MEK inhibitors confirmed ERK activation served as a mechanism of resistance to the lethal effects of pp242. Thus, although active site mTOR inhibitors overcome AKT activation often seen with rapalog therapy, feedback ERK activation is still a problem of resistance, is more severe than that seen with use of first generation rapalogs and is mediated by a TORC1- and eIF-4E-dependent mechanism ultimately signaling to RAF.
机译：PI3-K-AKT和ERK途径的激活是mTOR抑制剂治疗的并发症。新型的mTOR抑制剂（如pp242）可以克服多发性骨髓瘤（MM）细胞中AKT的反馈激活。因此，我们研究了在这种肿瘤模型中，ERK的反馈激活是否仍是此类药物治疗的并发症。 PP242在MM细胞系和原代细胞中诱导ERK激活。出乎意料的是，等摩尔浓度的雷帕霉素在ERK激活上相对无效。激活与P70S6激酶抑制作用无关，也不受PI3-激酶抑制作用阻止。 MEK抑制剂可阻止ERK活化，并与同时刺激RAF激酶活性相关，而与RAS活化无关。 RAF激活与Ser-289，Ser-296和Ser-301抑制残基处RAF的磷酸化降低有关。击倒研究证实，TORC1抑制是导致ERK激活的关键近端事件。此外，eIF-4E的异位表达使pp242诱导的ERK磷酸化变钝。由于pp242在隔离eIF-4E方面比雷帕霉素更有效，因此TORC1 / 4E-BP1 / eIF-4E介导的ERK激活机制可以解释pp242的更大功效。使用MEK抑制剂已证实ERK活化是对pp242致死作用的抗性机制。因此，尽管活性位点mTOR抑制剂克服了雷帕洛单抗治疗中常见的AKT激活，但反馈ERK活化仍然是耐药性的问题，比使用第一代雷帕洛单抗所看到的更为严重，并由TORC1-和eIF-4E-介导。依赖机制最终向RAF发出信号。

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