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

// Daphne Brisard 1, 2 , Frank Eckerdt 1, 3 , Lindsey A. Marsh 1, 2 , Gavin T. Blyth 1, 4 , Sarika Jain 1, 4 , Massimo Cristofanilli 1, 4 , Dai Horiuchi 1, 2 and Leonidas C. Platanias 1, 4, 5 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA 2 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 3 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 4 Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 5 Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois, USA Correspondence to: Leonidas C. Platanias, email: l-platanias@northwestern.edu Keywords: triple-negative breast cancer (TNBC); cancer stem-like cells; CDK9; MYC; atuveciclib Received: October 23, 2018      Accepted: December 04, 2018      Published: December 18, 2018 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 CD24 low /CD44 high 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.