The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.
The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.
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有丝分裂检查点是卡铂耐药三阴性乳腺癌的可靶向脆弱性。
DOI：
10.1038/s41598-021-82780-6
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发表时间：
2021-02-04
影响因子：
4.6
通讯作者：
Amant F
中科院分区：
文献类型：
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作者：
Moens S;Zhao P;Baietti MF;Marinelli O;Van Haver D;Impens F;Floris G;Marangoni E;Neven P;Annibali D;Sablina AA;Amant F
三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚型，缺乏有效的治疗方法。许多TNBCs对以卡铂为基础的化疗表现出显著的反应，但随着时间的推移往往会产生耐药性。随着卡铂在临床上的使用越来越多，迫切需要识别卡铂耐药肿瘤的脆弱性。在这项研究中，我们建立了对卡铂耐药的TNBC MDA-MB-468细胞系和患者来源的TNBC异种移植模型。基于质谱学的蛋白质组图谱显示，TNBC对卡铂的耐药性与剧烈的新陈代谢、重新布线和上调抗氧化反应有关，后者通过在卡铂存在的情况下维持低水平的DNA损伤来支持细胞复制。卡铂耐药细胞也表现出有丝分裂检查点的失调。动态组shRNA筛选显示，卡铂耐药细胞容易受到有丝分裂检查点调节因子耗尽的影响，而检查点激酶CHEK1和WEE1是卡铂耐药细胞在卡铂存在下生存所必需的。我们证实，在卡铂存在的情况下，Prexasertib对CHEK1的药理抑制作用在小鼠中具有良好的耐受性，并抑制卡铂耐药的TNBC异种移植瘤的生长。因此，通过CHEK1抑制取消有丝分裂检查点可以使卡铂耐药的TNBCs对卡铂重新敏感，这代表了治疗卡铂耐药的TNBCs的一种潜在策略。
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
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影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
5.1
作者：
Li, Qing;Wang, Jiani;Xu, Binghe
通讯作者：
Xu, Binghe
影响因子：
45.3
作者：
Hong, David;Infante, Jeffrey;Bendell, Johanna
通讯作者：
Bendell, Johanna
影响因子：
168.9
作者：
Denkert, Carsten;Liedtke, Cornelia;von Minckwitz, Gunter
通讯作者：
von Minckwitz, Gunter
影响因子：
9
作者：
通讯作者：
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