Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer


The cover for issue 99 of Oncotarget features Figure 1C, "Schematic representation of atuveciclib mode of action," by Brisard, et al.

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.

"Breast tumor subtypes are defined based on the expression of three primary identifiers: estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2."

Breast tumors lacking all three markers are referred to as triple-negative breast cancer, which account for 15 20% of all breast cancer cases.

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.

Figure 1:  CDK9 expression in TNBC patients and cell lines. ( A

Figure 1: CDK9 expression in TNBC patients and cell lines. (A) Kaplan-Meier analysis for overall survival rate based on CDK9 mRNA expression, RNA-seq data from a TCGA-cohort of 89 TNBC patients is shown. Log-rank (Mantel-Cox), p = 0.017. A list of sample IDs is provided in the supplement. (B) TNBC cell lines (n = 23) from the Neve_2006 dataset were analyzed for CDK9 expression. Gene expression data from Xena Browser (https://xenabrowser.net/) were ranked using GraphPad Prism. (C) Schematic representation of atuveciclib mode of action. (D) Comparison of atuveciclib IC50 values (see Supplementary Figure 2) between CDK9-high (n = 4) and – low (n = 4) TNBC cell lines. t-test was performed. *P < 0.05. (E) Log relative CDK9 expression of TNBC cell lines (n = 8), as determined in (B) versus atuveciclib IC50 from Supplementary Figure 2. Correlation was assessed using Spearman test (r = –0.8095, P = 0.0218).

This suggests important roles for CDKs in breast cancer invasion and metastasis, but, the precise contribution of each CDK in TNBC tumorigenesis remains to be defined.

We found that elevated CDK9 expression was associated with decreased progression-free survival in breast cancer patients and a worse overall survival among patients with TNBC. In TNBC cell lines exhibiting elevated CDK9 expression, atuveciclib potently inhibited cell proliferation and induced cell death.

"Using atuveciclib, a small molecule that selectively targets CDK9, we found that CDK9 targeting reduced cell proliferation and triggered apoptosis in high-CDK9 TNBC cells.

The present study provides evidence that atuveciclib suppresses the invasive cellular phenotype of high-CDK9 TNBC cells and disrupts the activities of CSLCs in 3D mammospheres, a cell population with high cellular demand for CDK9 activity.

These observations on the effects of a small molecule CDK9 inhibition on CSLCs are important new insights in TNBC, and are consistent with CDK9 loss-of-function phenotypes observed in glioblastoma stem cells.

Finally, we found that CDK9 inhibition by atuveciclib increased sensitivity of TNBC cells to cytotoxic chemotherapeutic agents."

Full text - https://doi.org/10.18632/oncotarget.26468

Correspondence to - Leonidas C. Platanias - [email protected]

Keywords - triple-negative breast cancer (TNBC), cancer stem-like cells, CDK9, MYC, atuveciclib

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