Selective inhibition of CDK9 in triple negative breast cancer.

Autor: Mustafa EH; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Laven-Law G; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Kikhtyak Z; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Nguyen V; Department of Surgery & Cancer, Imperial College London, London, UK., Ali S; Department of Surgery & Cancer, Imperial College London, London, UK., Pace AA; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Iggo R; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.; Institut Bergonié, University of Bordeaux, Bordeaux, France., Kebede A; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Noll B; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Wang S; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Winter JM; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Dwyer AR; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Tilley WD; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Hickey TE; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia. theresa.hickey@adelaide.edu.au.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Jan; Vol. 43 (3), pp. 202-215. Date of Electronic Publication: 2023 Nov 24.
DOI: 10.1038/s41388-023-02892-3
Abstrakt: Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC 50 range: 281-734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC 50 range: 272-771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.
(© 2023. The Author(s).)
Databáze: MEDLINE
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