A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine

Walsby, Elisabeth; Pratt, Guy; Shao, Hao; Abbas, Abdullah Y.; Fischer, Peter; Bradshaw, Tracey D.; Brennan, Paul; Fegan, Chris; Wang, Shudong; Pepper, Chris

Abstract

Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed >200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics.

Citation

Walsby, E., Pratt, G., Shao, H., Abbas, A. Y., Fischer, P., Bradshaw, T. D., Brennan, P., Fegan, C., Wang, S., & Pepper, C. (2013). A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget, 5, 375-385

• Journal Article Type: Article
• Acceptance Date: Dec 18, 2013
• Publication Date: Dec 18, 2013
• Deposit Date: Oct 26, 2017
• Publicly Available Date: Nov 19, 2018
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Pages: 375-385
• Public URL: https://nottingham-repository.worktribe.com/output/1110210
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=1568&path[]=1833
• Contract Date: Nov 19, 2018