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<p>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 <i>BRCAness</i> 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 <i>BRCAness</i> induction, but fails to achieve synergistic effects with cisplatin or olaparib in OC cells.</p>

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Absence of synergistic effects by CDK12/13 inhibition in combination with cisplatin or olaparib in ovarian cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Frédéric R. Santer,
  • Lea Hovdar,
  • Florian Handle,
  • Irina Tsibulak,
  • Verena Wieser,
  • Michael J. Ausserlechner,
  • Walther Parson,
  • Simon Schnaiter,
  • Alain G. Zeimet,
  • Christian Marth,
  • Heidelinde Fiegl

摘要

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.