Combined venetoclax and alvocidib in acute myeloid leukemia.
Combined venetoclax and alvocidib in acute myeloid leukemia.
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DOI：
10.18632/oncotarget.22284
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发表时间：
2017-12-05
期刊：
影响因子：
--
通讯作者：
Tibes R
中科院分区：
文献类型：
--
作者：
Bogenberger J;Whatcott C;Hansen N;Delman D;Shi CX;Kim W;Haws H;Soh K;Lee YS;Peterson P;Siddiqui-Jain A;Weitman S;Stewart K;Bearss D;Mesa R;Warner S;Tibes R
老年急性髓系白血病 (AML) 患者需要更有效的治疗方案，因为只有 25-50% 的患者对标准治疗有反应，反应持续时间通常很短，而且即使采用一些新疗法和正在进行的临床试验，疾病进展也是不可避免的。抗凋亡 BCL-2 家族抑制剂，例如 Venetoclax，是治疗 AML 的有前途的疗法。尽管如此，阻力正在出现。我们证明，venetoclax 与细胞周期蛋白依赖性激酶 (CDK) 抑制剂 alvocidib 联合使用，在体外、离体和体内的 venetoclax 敏感和耐药 AML 模型中具有有效的协同作用。 Alvocidib 可降低 MCL-1，和/或增加促凋亡蛋白（如 BIM 或 NOXA），通常与 Venetoclax 具有协同作用。 BCL-XL 的过度表达减弱了协同作用，而 BIM 的敲低几乎完全消除了协同作用，表明 alvocidib 和 venetoclax 之间的协同相互作用主要依赖于内在细胞凋亡。 CDK9 抑制主要介导 Venetoclax 致敏，而 Palbociclib 抑制 CDK4/6 不会增强 Venetoclax 活性。 venetoclax 和 alvocidib 相结合，通过有利于细胞凋亡的互补但可变的机制调节 BCL-2 家族蛋白的平衡，突显这种组合作为 AML 或高风险 MDS 的有前景的治疗方法，具有克服内在细胞凋亡机制的能力。这些结果支持维奈托克和阿沃西迪联合治疗 AML 和晚期 MDS 的临床测试。
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25–50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
11.2
作者：
Chen S;Dai Y;Pei XY;Myers J;Wang L;Kramer LB;Garnett M;Schwartz DM;Su F;Simmons GL;Richey JD;Larsen DG;Dent P;Orlowski RZ;Grant S
通讯作者：
Grant S
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
--
作者：
Bodo J;Zhao X;Durkin L;Souers AJ;Phillips DC;Smith MR;Hsi ED
通讯作者：
Hsi ED
影响因子：
4.6
作者：
Lin KH;Winter PS;Xie A;Roth C;Martz CA;Stein EM;Anderson GR;Tingley JP;Wood KC
通讯作者：
Wood KC