Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition.
Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition.
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非整倍性使癌细胞容易受到有丝分裂检查点抑制。
DOI：
10.1038/s41586-020-03114-6
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发表时间：
2021-03
期刊：
影响因子：
64.8
通讯作者：
Ben-David U
中科院分区：
文献类型：
--
作者：
Cohen-Sharir Y;McFarland JM;Abdusamad M;Marquis C;Bernhard SV;Kazachkova M;Tang H;Ippolito MR;Laue K;Zerbib J;Malaby HLH;Jones A;Stautmeister LM;Bockaj I;Wardenaar R;Lyons N;Nagaraja A;Bass AJ;Spierings DCJ;Foijer F;Beroukhim R;Santaguida S;Golub TR;Stumpff J;Storchová Z;Ben-David U
选择性靶向非整倍体细胞是治疗癌症的一种有吸引力的策略。在这里，我们绘制了大约1000个人类癌细胞系的非整倍体图谱，并分析了遗传和化学扰动筛选，以揭示与非整倍体相关的细胞脆弱性。我们鉴定并验证了非整倍体癌细胞对纺锤体组装检查点(SAC)核心组件的遗传扰动的敏感性增加，这确保了有丝分裂过程中染色体的适当分离。令人惊讶的是，我们还发现非整倍体癌细胞对短期暴露于多种SAC抑制剂的敏感性较低。事实上，随着时间的推移，非整倍体癌细胞对SAC抑制(SACI)越来越敏感。非整倍体细胞表现出异常的纺锤体几何形状和动力学，并在SACI存在的情况下持续分裂，导致累积的有丝分裂缺陷，以及不稳定和不太适合的核型。因此，尽管非整倍体癌细胞比二倍体细胞更容易克服SACI，但它们的长期增殖受到了威胁。我们鉴定了一种特殊的有丝分裂激动素KIF18A，它的活性在非整倍体癌细胞中受到干扰。非整倍体癌细胞特别容易受到KIF18A缺失的影响，KIF18A过表达恢复了它们对SACI的反应。我们的研究揭示了非整倍体和SAC之间一种新颖的、与治疗相关的、人工合成的致命性相互作用。
Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines, and analyzed genetic and chemical perturbation screens to reveal aneuploidy-associated cellular vulnerabilities. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found aneuploid cancer cells to be less sensitive to short-term exposures to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly more sensitive to SAC inhibition (SACi) over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing in the presence of SACi, resulting in accumulating mitotic defects, and in unstable and less fit karyotypes. Therefore, although aneuploid cancer cells could overcome SACi more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored their response to SACi. Our study reveals a novel, therapeutically-relevant, synthetic lethal interaction between aneuploidy and the SAC.
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影响因子：
4.4
作者：
Dürrbaum M;Kuznetsova AY;Passerini V;Stingele S;Stoehr G;Storchová Z
通讯作者：
Storchová Z
影响因子：
2.7
作者：
Czechanski, Anne;Kim, Haein;Byers, Candice;Greenstein, Ian;Stumpff, Jason;Reinholdt, Laura G.
通讯作者：
Reinholdt, Laura G.
影响因子：
7.7
作者：
Hieronymus H;Murali R;Tin A;Yadav K;Abida W;Moller H;Berney D;Scher H;Carver B;Scardino P;Schultz N;Taylor B;Vickers A;Cuzick J;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
4
作者：
Braun, Joachim;Moeckel, Martin M.;Mayer, Thomas U.
通讯作者：
Mayer, Thomas U.