Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition.
Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition.
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氧化磷酸化的调节增强有丝分裂极光激酶抑制的抗肿瘤活性
DOI：
10.1038/s41419-021-04190-w
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发表时间：
2021-09-30
影响因子：
9
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Zhang Z;Zeng D;Zhang W;Chen A;Lei J;Liu F;Deng B;Zhuo J;He B;Yan M;Lei X;Wang S;Lam EW;Liu Q;Wang Z
无控制的有丝分裂是癌症最重要的特征之一，有丝分裂酶被认为是抗癌治疗的理想靶点。然而，尽管数十年来进行了许多临床尝试，但由于治疗效果有限，有丝分裂激酶靶向剂的临床试验通常在后期停滞不前。Alisertib(MLN8237)是一种很有前途的口服有丝分裂极光激酶A(AURKA，Aurora-A)选择性抑制剂，目前正在进行多项临床评估，但由于疗效不佳，其第一阶段III试验失败。在这项研究中，我们进行了全基因组CRISPR/CAS9筛查，以确定乳腺癌MDA-MB-231细胞中与泽泻替布相关的脆弱生物学过程。结果表明，艾利昔布处理的癌细胞对氧化磷酸化(OXPHOS)的遗传扰动更敏感。机制研究表明，alisertib治疗，以及其他有丝分裂酶抑制剂，迅速降低细胞内ATP水平，以产生对OXPHOS高度上瘾的状态。此外，Alisertib和二甲双胍分别联合抑制有丝分裂酶和OXPHOS，在有丝分裂细胞中产生严重的能量耗竭，从而触发细胞死亡。联合方案在体内也显著地促进了肿瘤的消退。这表明二甲双胍靶向OXPHOS是一种潜在的通过联合靶向有丝分裂和细胞能量平衡来提高有丝分裂酶抑制剂的治疗效果的策略。
Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.
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DOI：
10.1126/science.aal4671
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Palozola KC;Donahue G;Liu H;Grant GR;Becker JS;Cote A;Yu H;Raj A;Zaret KS
通讯作者：
Zaret KS
影响因子：
8
作者：
Brown, Jason R.;Chan, Daniel K.;Buckanovich, Ronald J.
通讯作者：
Buckanovich, Ronald J.
影响因子：
7.7
作者：
Bertolin G;Bulteau AL;Alves-Guerra MC;Burel A;Lavault MT;Gavard O;Le Bras S;Gagné JP;Poirier GG;Le Borgne R;Prigent C;Tramier M
通讯作者：
Tramier M
DOI：
10.1083/jcb.19.2.267
发表时间：
1963-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
KONRAD CG
通讯作者：
KONRAD CG
CRISPR/Cas9 筛选确定了乳腺癌中 Aurora-A 抑制剂耐药性的动粒微管依赖性机制。
DOI：
10.1002/cac2.12125
发表时间：
2021-03
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Chen A;Wen S;Liu F;Zhang Z;Liu M;Wu Y;He B;Yan M;Kang T;Lam EW;Wang Z;Liu Q
通讯作者：
Liu Q