The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis.
The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis.
复制标题
HER2 抑制剂 TAK165 通过激活 MEK/ERK 介导的 RARα/STAT1 轴使人急性髓系白血病细胞对视黄酸诱导的髓系分化敏感
DOI：
10.1038/srep24589
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发表时间：
2016-04-14
影响因子：
4.6
通讯作者：
He Q
中科院分区：
文献类型：
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作者：
Shao X;Liu Y;Li Y;Xian M;Zhou Q;Yang B;Ying M;He Q
全反式维甲酸(ATRA)在急性早幼粒细胞白血病(APL)分化治疗中的成功，极大地鼓励了研究将该疗法应用于其他类型的急性髓系白血病(AML)。然而，除APL外，AML对分化治疗均无反应。因此，迫切需要研究策略来进一步使细胞对维甲酸敏感，并将对维甲酸反应的AML的范围扩大到APL之外。在这项研究中，我们发现HER2抑制剂TAK165与ATRA在促进AML细胞分化方面表现出很强的协同作用。我们观察到TAK165使AML细胞对ATRA诱导的细胞生长抑制、G0/G1期停滞、CD11b表达、成熟形态改变、NBT减少和髓系调节因子表达敏感。意外的是，当与全反式维甲酸联合使用时，HER2通路可能不是TAK165增强分化所必需的，而增强的分化依赖于RARα/STAT1轴的激活。此外，MEK/ERK级联信号调节STAT1的激活。综上所述，我们的研究首次评估了TAK165和ATRA在AML细胞分化中的协同作用，并评估了TAK165和ATRA联合作为未来分化治疗的一种有前途的方法的新机会。
The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). However, AML, with the exception of APL, fails to respond to differentiation therapy. Therefore, research strategies to further sensitize cells to retinoids and to extend the range of AMLs that respond to retinoids beyond APLs are urgently needed. In this study, we showed that TAK165, a HER2 inhibitor, exhibited a strong synergy with ATRA to promote AML cell differentiation. We observed that TAK165 sensitized the AML cells to ATRA-induced cell growth inhibition, G0/G1 phase arrest, CD11b expression, mature morphologic changes, NBT reduction and myeloid regulator expression. Unexpectedly, HER2 pathway might not be essential for TAK165-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of the RARα/STAT1 axis. Furthermore, the MEK/ERK cascade regulated the activation of STAT1. Taken together, our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy.