Transcriptomic analysis (RNA-seq) of BRCA1-proficient and BRCA1-deficient ovarian cancer cells treated with the triazene compound CT913 and its metabolite CT913-M1

ABSTRACT: Extending the therapeutic spectrum of PARP-inhibition (PARPi) beyond HR-deficiency or reverting PARPi resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a promising strategy for defining new therapeutic standards. In this study, we analysed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with PARPi. This is the first study analysing the potential therapeutic effect of these components. In vitro assays for drug characterization including RNA-seq were applied in a selected panel of ovarian cancer cell lines. CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the micro- to almost millimolar range (107-940µM), whereas its metabolite CT913-M1 was about 10-fold more potent (IC50 of 17-93µM). Neither of the drugs increased the cytotoxic effect of cisplatin, CT913 might even antagonize it. Furthermore, CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that homologues recombination (HR) repair may contribute to its mechanism of action. Importantly, CT913 sensitized for olaparib treatment, independently of BRCA-1 mutational status, supporting the finding that CT913 may act partially independent of an impaired HR. CT913 treatment led to changes in gene transcription. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It also downregulated a variety of transcripts involved in prominent DNA-repair pathways, such as HR, mismatch repair (MMR) or nucleotide excision repair (NER). This is the first study, suggesting the triazene drug class CT913 as auxiliary drug for extending the therapeutic spectrum of PARPi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150377 | GEO | 2021/05/31

REPOSITORIES: GEO