MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma.
MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma.
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DOI：
10.1158/1535-7163.mct-14-0711
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发表时间：
2015-02
影响因子：
5.7
通讯作者：
Schwartz GK
中科院分区：
文献类型：
--
作者：
Slotkin EK;Patwardhan PP;Vasudeva SD;de Stanchina E;Tap WD;Schwartz GK
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸蛋白激酶，存在于两种复合物（mTORC 1和mTORC 2）中，整合细胞外和细胞内信号，作为细胞生长、存活和代谢的主要调节因子。PI 3 K/AKT/mTOR促生存通路在多种肉瘤亚型中经常失调。mTORC 1的第一代变构抑制剂（rapalogues）已被广泛测试，具有很大的临床前前景，但临床实用性有限。在此，我们报告了MLN 0128，一种第二代ATP竞争性泛mTOR激酶抑制剂，作用于mTORC 1和mTORC 2，在多种肉瘤亚型中具有强效的体外和体内抗肿瘤活性。在体外，MLN 0128以浓度依赖性方式抑制mTORC 1/2靶点，并在横纹肌肉瘤（RMS）、尤文肉瘤（ES）、恶性外周神经鞘瘤、滑膜肉瘤、骨肉瘤和脂肪肉瘤中显示出显著的抗增殖作用。与雷帕霉素不同，MLN 0128可抑制4 EBP 1和NDRG 1的磷酸化，并可防止pAKT的再激活，pAKT的再激活是通过单独抑制mTORC 1的负反馈释放发生的。在异种移植模型中，MLN 0128给药导致两种给药方案（1 mg/kg每日一次和3 mg/kg BID TIW）抑制肿瘤生长。在RMS和ES模型中，MLN 0128给药方案为3 mg/kg时，肿瘤生长抑制效果显著优于雷帕霉素。此外，MLN 0128在体外和体内RMS模型中诱导细胞凋亡。我们的研究结果强烈表明，应进一步探索MLN 0128治疗作为肉瘤的潜在治疗方法。
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR pro-survival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great pre-clinical promise, but have had limited clinical utility. Here we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2, and has potent in vitro and in vivo anti-tumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration dependent fashion, and shows striking anti-proliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma (ES), malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg BID TIW). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and ES models. Additionally, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma.