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首页> 外文期刊>Cell cycle >Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in acute myeloid leukemia.
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Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in acute myeloid leukemia.

机译：厄洛替尼拮抗急性髓细胞性白血病中SRC家族激酶和mTOR的组成型激活。

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摘要

Tyrosine kinases such as SRC family kinases (SFKs) as well as the mammalian target of rapamycin (mTOR) serine/threonine kinase are often constitutively activated in acute myeloid leukemia (AML) and hence constitute potential therapeutic targets. Here we demonstrate that the epidermal growth factor receptor (EGFR) inhibitor erlotinib, which has previously been shown to mediate antiproliferative/cytotoxic off-target effects in myelodysplastic syndrome (MDS) and AML blasts, reduces SFK overactivation. Erlotinib induced an arrest in the G 1 phase of the cell cycle that, in cells with constitutive SFK activation, could be recapitulated by chemical inhibition of SFKs with 3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-alpha]pyrimidin-4-amine (PP2). Moreover, erlotinib inhibited the phosphorylation of mTOR targets like p70 (SK6) , stimulated the maturation of the autophagic marker LC3 and promoted the formation of autophagosomes. Notably, PP2 and the mTOR inhibitor rapamycin had a similar cell cycle-arresting activity to erlotinib, but neither of these compounds alone induced significant levels of cell death. Altogether, these results suggest that the therapeutic off-target effect of erlotinib may be linked to, yet cannot be entirely explained by, the inhibition of oncogenic signaling via SFKs and mTOR. Thus, combination therapies with erlotinib and rapamycin might be beneficial for MDS and AML patients.
机译：酪氨酸激酶（例如SRC家族激酶（SFK））以及哺乳动物雷帕霉素靶标（mTOR）丝氨酸/苏氨酸激酶通常在急性髓细胞白血病（AML）中被组成型激活，因此构成潜在的治疗靶标。在这里，我们证明了表皮生长因子受体（EGFR）抑制剂厄洛替尼（以前已被证明在骨髓增生异常综合症（MDS）和AML原始细胞中介导抗增殖/细胞毒性脱靶效应，可减少SFK过度活化。厄洛替尼诱导了细胞周期G 1期的阻滞，在具有组成性SFK激活的细胞中，可以通过化学抑制SFK的作用来重现3-K-（4-氯苯基）1-（1,1-二甲基乙基）-1H-吡唑并[3,4-α]嘧啶-4-胺（PP2）。此外，厄洛替尼抑制mTOR靶标如p70（SK6）的磷酸化，刺激自噬标记物LC3的成熟并促进自噬体的形成。值得注意的是，PP2和mTOR抑制剂雷帕霉素具有与厄洛替尼相似的细胞周期阻滞活性，但是单独使用这两种化合物都不会引起明显的细胞死亡。总而言之，这些结果表明，厄洛替尼的脱靶治疗作用可能与通过SFK和mTOR抑制致癌信号有关，但不能完全解释。因此，埃罗替尼和雷帕霉素的联合疗法可能对MDS和AML患者有益。

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