Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.
Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.
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DOI：
10.1038/s41389-021-00357-4
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发表时间：
2021-10-12
期刊：
影响因子：
6.2
通讯作者：
Kyba M
中科院分区：
文献类型：
--
作者：
Bosnakovski D;Ener ET;Cooper MS;Gearhart MD;Knights KA;Xu NC;Palumbo CA;Toso EA;Marsh GP;Maple HJ;Kyba M
CIC-DUX 4肉瘤（CDS）是一种高度侵袭性和转移性的小圆型主要是儿科肉瘤，由融合癌蛋白驱动，该融合癌蛋白包含与DUX 4的C-末端转录激活结构域融合的转录阻遏物Capicua（CIC）。CDS对化疗迅速产生耐药性，因此非常需要新的特异性治疗。我们证明，CIC-DUX 4需要P300/CBP诱导组蛋白H3乙酰化，激活其靶点，并驱动肿瘤发生。我们描述了一种选择性和高效的P300/CBP抑制剂iP 300 w和相关的立体异构体的合成路线，发现iP 300 w有效地抑制CIC-DUX 4的转录活性并逆转CIC-DUX 4诱导的乙酰化。iP 300 w在比相关立体异构体或A-485低100倍的浓度下具有活性。在低剂量下，iP 300 w显示出对CDS癌细胞系的特异性，在体内递送时快速诱导细胞周期停滞并防止已建立的CDS异种移植肿瘤的生长。iP 300 w对CDIC-DUX 4的有效性突出了CDS的有希望的治疗机会。
CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.
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影响因子：
64.8
作者：
Lasko LM;Jakob CG;Edalji RP;Qiu W;Montgomery D;Digiammarino EL;Hansen TM;Risi RM;Frey R;Manaves V;Shaw B;Algire M;Hessler P;Lam LT;Uziel T;Faivre E;Ferguson D;Buchanan FG;Martin RL;Torrent M;Chiang GG;Karukurichi K;Langston JW;Weinert BT;Choudhary C;de Vries P;Van Drie JH;McElligott D;Kesicki E;Marmorstein R;Sun C;Cole PA;Rosenberg SH;Michaelides MR;Lai A;Bromberg KD
通讯作者：
Bromberg KD
影响因子：
5.4
作者：
Li Y;Seto E
通讯作者：
Seto E
影响因子：
5.6
作者：
Choi, Eun-Young Karen;Thomas, Dafydd G.;Lucas, David R.
通讯作者：
Lucas, David R.
DOI：
10.1073/pnas.0401002101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Iyer, NG;Chin, SF;Caldas, C
通讯作者：
Caldas, C
影响因子：
3.5
作者：
Gabriëls, J;Beckers, MC;Belayew, A
通讯作者：
Belayew, A