Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer.
Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer.
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DOI：
10.18632/oncotarget.26468
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发表时间：
2018-12-18
期刊：
影响因子：
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通讯作者：
Platanias, Leonidas C
中科院分区：
文献类型：
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作者：
Brisard, Daphne;Eckerdt, Frank;Platanias, Leonidas C
由于缺乏有效的靶向治疗，三阴性乳腺癌（TNBC）的治疗选择受到限制，经常导致复发和转移。越来越多的证据表明，一小群癌症干细胞样细胞（CSLC）是导致肿瘤复发和治疗耐药的原因。在这里，我们研究了细胞周期蛋白依赖性激酶 9 (CDK9) 在 TNBC 中的作用。使用癌症基因组图谱 (TCGA) 数据，我们发现高 CDK9 表达与 TNBC 患者较差的总体生存率相关。在高 CDK9 表达的 TNBC 细胞系中，使用 atuveciclib 对 CDK9 进行药理学抑制，可降低 CDK9 靶标 MYC 和 MCL1 的表达，并降低细胞增殖和存活。重要的是，atuveciclib 抑制乳腺球的生长并降低 CD24low/CD44high 细胞的百分比，表明乳腺 CSLC (BCSLC) 受到破坏。此外，atuveciclib 损害了肿瘤球的 3D 侵袭，表明抑制了侵袭和转移潜力。最后，atuveciclib 增强了顺铂的抗肿瘤作用，并促进了对以乳腺球形式生长的 BCSLC 的抑制作用。总之，这些发现表明 CDK9 作为侵袭性 CDK9 高 TNBC 的潜在治疗靶点。
Treatment options for triple-negative breast cancer (TNBC) are limited due to the lack of efficient targeted therapies, frequently resulting in recurrence and metastatic disease. Accumulating evidence suggests that a small population of cancer stem-like cells (CSLCs) is responsible for tumor recurrence and therapy resistance. Here we investigated the role of cyclin-dependent kinase 9 (CDK9) in TNBC. Using The Cancer Genome Atlas (TCGA) data we found high-CDK9 expression correlates with worse overall survival in TNBC patients. Pharmacologic inhibition of CDK9 with atuveciclib in high-CDK9 expressing TNBC cell lines reduced expression of CDK9 targets MYC and MCL1 and decreased cell proliferation and survival. Importantly, atuveciclib inhibited the growth of mammospheres and reduced the percentage of CD24low/CD44high cells, indicating disruption of breast CSLCs (BCSLCs). Furthermore, atuveciclib impaired 3D invasion of tumorspheres suggesting inhibition of both invasion and metastatic potential. Finally, atuveciclib enhanced the antineoplastic effects of Cisplatin and promoted inhibitory effects on BCSLCs grown as mammospheres. Together, these findings suggest CDK9 as a potential therapeutic target in aggressive forms of CDK9-high TNBC.