The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737
The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737
复制标题
DOI：
10.1158/1535-7163.mct-16-0342
复制
发表时间：
2017-01-01
影响因子：
5.7
通讯作者：
Villedieu, Marie
中科院分区：
文献类型：
--
作者：
Petigny-Lechartier, Cecile;Duboc, Charlene;Villedieu, Marie
新的治疗策略的识别是卵巢癌的临床管理的一个重要的迫切要求，卵巢癌仍然是妇科癌症死亡的主要原因。几项研究表明，抗凋亡蛋白Bcl-xL和Mcl-1，以及促凋亡蛋白Bim，是被调节以杀死卵巢癌细胞的关键因素。Bcl-xL的药理学抑制是可能的，通过使用BH 3-模拟分子，如ABT-737。然而，抑制Mcl-1和/或促进其仅有BH 3的伴侣（包括Bim、Puma和Noxa）仍然是一个挑战，可以通过调节上游信号传导途径来实现。本研究旨在探讨AZD 8055诱导的mTOR抑制和/或曲美替尼诱导的MEK抑制是否可以调节Mcl-1及其伴侣，以降低Mcl-1/BH 3-only比率，从而使各种卵巢癌细胞系对ABT-737敏感。AZD 8055处理抑制Mcl-1并增加Puma表达，但与ABT-737组合不诱导大量凋亡。相反，曲美替尼通过上调Puma和去磷酸化活性Bim降低Mcl-1/BH 3-only蛋白比例，使IGROV 1-R10和OVCAR 3细胞对ABT-737敏感。在IGROV 1-R10细胞中，将AZD 8055添加到曲美替尼中进一步降低了Mcl-1/BH 3-only蛋白的比例，并在没有ABT-737的情况下引发了细胞凋亡。此外，AZD 8055/曲美替尼联合使所有细胞系（包括SKOV 3）对ABT-737高度致敏，诱导的去磷酸化Bim在这种致敏中至关重要。最后，当用泛Akt抑制剂MK-2206代替AZD 8055时，三种药物组合也非常有效。因此，这项研究提出了原始的多靶向策略，并可能对卵巢癌治疗新方法的设计具有重要意义。(C)2016年AACR。
The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancer, which remains the leading cause of death from gynecologic cancer. Several studies have shown that the antiapoptotic proteins Bcl-xL and Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-xL is possible by using BH3-mimetic molecules like ABT-737. However, inhibition of Mcl-1 and/or promotion of its BH3-only partners (including Bim, Puma, and Noxa) remains a challenge that may be achieved by modulating the signaling pathways upstream. This study sought whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl-1/BH3-only protein ratio and triggered apoptosis without ABT-737 in IGROV1-R10 cells. Moreover, the AZD8055/trametinib association highly sensitized all cell lines includingSKOV3to ABT-737, the induced dephosphorylated Bim being crucial in this sensitization. Finally, the three-drug combination was also very efficient when replacing AZD8055 by the pan-Akt inhibitor MK-2206. This study thus proposes original multitargeted strategies and may have important implications for the design of novel approaches for ovarian cancer treatment. (C) 2016 AACR.