Abstract
The identification of novel molecular drivers and the development of new state-of-the-art therapies are critical challenges in ovarian cancer (OC) treatment. Cyclin-dependent kinase 12 (CDK12) is a promising target, as it’s functional activity promotes genomic stability. Here, we examined the anticancer efficacy of the dual CDK12/13-inhibitor SR-4835 in platinum-sensitive and -resistant OC cell lines, as well as its potential as a drug partner for platinum or olaparib combination therapy. SR-4835 exhibited potent anti-proliferative effects on most OC cell lines with IC50 values within the nanomolar range. A tendency for increased sensitivity of the cisplatin-resistant compared to their sensitive, parental cell lines was observed. Transcriptome analyses indicated gross changes in gene expression in numerous signaling pathways by SR-4835. Gene downregulation was in part due to alternative exon usage, which correlated with the number of intronic polyadenylation sites per gene and gene length. Furthermore, SR-4835 lead to the downregulation of key homologous recombination pathway genes rendering a BRCAness phenotype. However, the combination of SR-4835 with cisplatin or olaparib primarily exhibited an additive, not synergistic, effect. In summary, the present findings indicate that CDK12/13 inhibitor SR-4835 has potent anti-cancer effects accompanied by a BRCAness induction, but fails to achieve synergistic effects with cisplatin or olaparib in OC cells.
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Data availability
The data supporting the findings of this study are provided in the Supplementary Information of this article or are available from the corresponding author upon request. The datasets generated and/or analysed during the current study are available in the ArrayExpress repository under accession number E-MTAB-15987 (https://www.ebi.ac.uk/biostudies/ArrayExpress/studies/E-MTAB-15987). Raw sequencing reads (FASTQ) can be retrieved from the European Nucleotide Archive under accession number PRJEB93935 (https://www.ebi.ac.uk/ena/browser/view/PRJEB93935).
Abbreviations
- CDK:
-
Cyclin-dependent kinase
- DDR:
-
DNA damage response
- HRD:
-
Homologous recombination repair deficiency
- MTT:
-
3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide
- OC:
-
Ovarian cancer
- PARP:
-
Poly (ADP-ribose) polymerase
- PARPi:
-
PARP inhibitors
- poly(A):
-
Polyadenylation
- qPCR:
-
QuantitaTive real-time PCR
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Acknowledgements
We thank Kathrin Ausserlechner, Brigitte Greiderer-Kleinlercher, Petra Hechenberger, Stefanie Rainer, Sarah Ritscher, Martin Fleisch and the team of the High Throughput DNA Database Laboratory, Institute of Legal Medicine, Medical University of Innsbruck for their excellent technical assistance and Kaisa Huhtinen, Olli Carpén and Robert Zeillinger for providing cell lines.
Funding
This work was supported by the Verein zur Krebsforschung in der Frauenheilkunde.
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H.F. and C.M. developed the concept and designed the study. L.H., F.H., F.S., I.T., V.W., M.J.A., W.P, S.S., A.G.Z., C.M., and H.F. were involved in the data acquisition and quality control of the data and algorithms. L.H., F.H., F.S., I.T., V.W., M.J.A., W.P, A.G.Z., C.M., and H.F. analyzed and interpreted the data. L.H., F.H., F.S and H.F. performed statistical analyses and prepared the manuscript. L.H., F.H., F.S., I.T., V.W., M.J.A., W.P, S.S., A.G.Z., C.M., and H.F. edited the manuscript and reviewed the final version.
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Santer, F.R., Hovdar, L., Handle, F. et al. Absence of synergistic effects by CDK12/13 inhibition in combination with cisplatin or olaparib in ovarian cancer cells. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46634-3
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DOI: https://doi.org/10.1038/s41598-026-46634-3
