Abstract
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.
Highlights
Breast tumor subtypes are defined based on the expression of three primary identifiers: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)
To investigate whether cyclin-dependent kinase 9 (CDK9) could be a therapeutic target for patients with triple-negative breast cancer (TNBC), we sought to explore the effects of the novel small molecule CDK9 inhibitor atuveciclib on TNBC cells
Consistent with the idea of different degrees of CDK9-dependency, we found that a panel of high-CDK9 expressing cell lines (e.g., MDA-MB-231, MDA-MB-436, MDA-MB-453, BT549) exhibited significantly higher sensitivity to atuveciclib as compared to a panel of low-CDK9 expressing cell lines (e.g., HCC1937, MDA-MB-157, HCC3153, HBL100) (Figure 1D and Supplementary Figure 2)
Summary
Breast tumor subtypes are defined based on the expression of three primary identifiers: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Treatment options for patients with TNBC are currently limited to the combinations of conventional chemotherapy in both primary and metastatic setting, radiation, and surgery in early disease [1, 2]. Evidence indicates that metastasis in various cancer types including breast cancer is promoted by a small subset of tumor cells termed cancer stem-like cells (CSLCs) [7]. These cells are pluripotent, able to self-renew, and eventually may give rise to malignant tumors [8, 9]. CSLCs mediate resistance to the current standard of care including chemotherapy and radiation, resulting in poor clinical outcomes [7, 10]
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