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

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.

CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

“…Most are associated with large enhancer regions occupied by multiple transcriptional factors, called super-enhancers. As a result, these genes are exceptionally active and sensitive to inhibitors targeting key regulators of transcription (e.g., CDK7 by THZ1 and CDK9 by BAY1143572 and dinaciclib) ( 156 , 157 , 208 ). Clinically, high CDK9 expression in TNBC patients renders comparatively poor overall survival ( 157 ).…”

“…BAY1143572 (atuveciclib), a benzyl sulfoximine, is one of the most selective and potent CDK9 inhibitors (IC 50 = 6 nM) currently being evaluated in clinical trials ( 192 ). The compound inhibited the proliferation of cancer cell lines at sub-micromolar concentrations and suppressed the growth of subcutaneous xenograft models of AML ( 134 , 192 ), TNBC ( 157 ), lymphoma ( 143 , 146 ), and esophageal ( 165 ) cancer. BAY1143572 inhibited the phosphorylation of RNAP II CTD on Ser2, downregulated MCL-1 and MYC, and induced apoptosis.…”

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

“…Notably, most clinical transcriptional CDK inhibitors have hit multiple CDKs. CDK9 has been shown to be a promising and druggable target in oncology for attenuating oncogenic transcription for a variety of indications (Blake et al, 2019;Brisard et al, 2018;Franco et al, 2018;Hashiguchi et al, 2019;Mitra et al, 2016;Morales and Giordano, 2016;Wang et al, 2019). However, as CDK9 also plays a global role in transcription, a sufficient therapeutic index for clinical benefit has not yet been demonstrated.…”

Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

“…CDK9 is found to be overexpressed in a variety of cancers including pancreatic [11], ovarian [12], cervical [13], esophageal [14] and osteosarcoma [15], with increased CDK9 correlated to poorer patient prognosis [11,15,12]. From in vitro studies and animal models, CDK9 has been implicated as a potential target for therapeutic intervention due to its role in MYC stabilization [16], chemo-and radio-resistance [17][18][19], and maintenance of cancer cell stemness [20,21]. While the lack of selectivity in most current CDK9 inhibitors has led to some trepidation regarding their use in the clinic [22], nonetheless a number of clinical candidates targeting CDK9 are being advanced in clinical trials addressing blood cancers, melanoma, glioblastoma, breast cancer, and other advanced solid tumors (clinicaltrials.gov).…”

“…dioxin-6-yl)methanone (12an). General method C was followed using 11(20 mg, 0.07 mmol.) and tricyclo[5.2.1.0,3,6]decan-8-amine (196 mg, 1.30 mmol.).…”