Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax.
Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax.
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靶向eIF4F翻译起始复合体SBI-756增强B淋巴瘤细胞对万乃馨的敏感性。
DOI：
10.1038/s41416-020-01205-9
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发表时间：
2021-03
影响因子：
8.8
通讯作者：
Fruman DA
中科院分区：
文献类型：
--
作者：
Herzog LO;Walters B;Buono R;Lee JS;Mallya S;Fung A;Chiu H;Nguyen N;Li B;Pinkerton AB;Jackson MR;Schneider RJ;Ronai ZA;Fruman DA
BCL 2抑制剂venetoclax已在几种血液恶性肿瘤中显示出疗效，在慢性淋巴细胞白血病等惰性血液癌症中的反应率最高。弥漫性大B细胞淋巴瘤（DLBCL）对维奈托克单药治疗的应答率较低。我们测试了帽依赖性mRNA翻译抑制剂使DLBCL和套细胞淋巴瘤（MCL）细胞对维奈托克引起的细胞凋亡敏感的能力。我们比较了mTOR激酶抑制剂（TOR-KI）MLN 0128与SBI-756，SBI-756是一种靶向真核翻译起始因子4G 1（eIF 4G 1）的化合物，eIF 4F复合物中的支架蛋白。用SBI-756处理DLBCL和MCL细胞与维奈托克在体外协同诱导细胞凋亡，并增强维奈托克在体内的功效。SBI-756阻止eIF 4 E-eIF 4G 1结合和帽依赖性翻译，而不影响mTOR底物磷酸化。在缺乏eIF 4 E结合蛋白-1的TOR-KI耐药DLBCL细胞中，SBI-756仍然对维奈托克敏感。SBI-756选择性地减少编码核糖体蛋白和翻译因子的mRNA的翻译，导致敏感细胞中蛋白质合成速率的降低。当用SBI-756处理正常淋巴细胞时，只有B细胞的活力降低，这与蛋白质合成减少有关。我们的数据突出了一种治疗侵袭性淋巴瘤的新组合，并使用临床前模型建立了其疗效和选择性。
The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL). We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex. Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis. Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.
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影响因子：
82.9
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
通讯作者：
Fruman, David A.
各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
影响因子：
28.2
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
11.2
作者：
Feng Y;Pinkerton AB;Hulea L;Zhang T;Davies MA;Grotegut S;Cheli Y;Yin H;Lau E;Kim H;De SK;Barile E;Pellecchia M;Bosenberg M;Li JL;James B;Hassig CA;Brown KM;Topisirovic I;Ronai ZA
通讯作者：
Ronai ZA
影响因子：
4.4
作者：
Chiu, Honyin;Jackson, Leandra V.;Fruman, David A.
通讯作者：
Fruman, David A.
影响因子：
64.8
作者：
Boussemart, Lise;Malka-Mahieu, Helene;Vagner, Stephan
通讯作者：
Vagner, Stephan