The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent.
The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent.
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mTORC1/2 双重抑制剂 INK-128 作为潜在抗结直肠癌药物的临床前评估。
DOI：
10.4161/15384047.2014.972274
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发表时间：
2015
影响因子：
3.6
通讯作者：
Lu PH
中科院分区：
文献类型：
--
作者：
Li C;Cui JF;Chen MB;Liu CY;Liu F;Zhang QD;Zou J;Lu PH
结直肠癌是癌症相关死亡率的主要贡献者。哺乳动物雷帕霉素靶蛋白（mTOR）存在于2种复合物（mTORC 1/2）中，在结直肠癌中经常失调并组成性激活。它是一个重要的药物靶点。在这里，我们发现，INK-128，一种新的ATP竞争性激酶抑制剂mTOR，阻断mTORC 1和mTORC 2在结直肠癌细胞（包括原代和转化细胞）的激活。免疫沉淀结果表明，mTORC 1（mTOR-Raptor缔合）和mTORC 2（mTOR-Rictor-Sin 1缔合）的组装也被INK-128破坏。INK-128抑制结肠直肠癌细胞生长和存活，并诱导凋亡和非凋亡癌细胞死亡。此外，INK-128对Erk/MAPK活化没有影响，而MEK-162对MEK/Erk的抑制增强了INK-128诱导的结直肠癌细胞的细胞毒性。同时，INK-128下调Fascin 1（FSCN 1）/E-Cadherin的表达，抑制HT-29细胞的体外迁移。在体内，每天口服给予INK-128抑制小鼠中的HT-29异种移植物生长，这通过给予MEK-162进一步增强。最后，我们发现，在体内和体外，INK-128敏化5-氟尿嘧啶-（5-FU）介导的抗HT-29活性。因此，我们的临床前研究强烈表明，INK-128可能在临床试验中用于结肠直肠癌治疗。
The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials.