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Background <p>Resistance to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a main limitation in breast cancer therapy. Identifying effective sensitizers is crucial to overcome this hurdle. Cyclin-dependent kinase-9 (CDK-9) inhibition has recently emerged as a potential strategy to enhance apoptotic responses in cancer cells.</p> Materials and methods <p>We investigated the effect of A09-003, a novel CDK9 inhibitor, on TRAIL-induced apoptosis and cell signaling in TNBC breast cancer cells. Cell viability was assessed by CellTiter-Glo assays, while apoptotic induction was evaluated using Flow cytometry analysis with Annexin V/PI staining, DNA fragmentation, and caspase activity assay. Protein expression levels of Mcl-1 and death receptors were analyzed via Western blotting and real time PCR. Mechanistic studies explored Mcl-1 protein degradation and transcriptional regulation through CDK-9 inhibition.</p> Results <p>A09-003 significantly enhanced TRAIL-induced apoptosis in tested breast cancer cells by increasing death receptor 5 expression, promoting caspase activation, and DNA fragmentation. Mechanistically, A09-003 downregulated Mcl-1 expression through dual pathways: promoting its proteasomal degradation and suppressing transcription via inhibition of CDK9-dependent RNA polymerase II phosphorylation.</p> Conclusion <p>A09-003 restores TRAIL sensitivity through Mcl-1 downregulation, identifying CDK-9 as a therapeutic target in resistant breast cancers.</p>

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CDK9 inhibitor A09-003 overcomes TRAIL resistance via dual Mcl-1 suppression in breast cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月5日

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  • Kyoung Mi Sim,
  • Supyong Hwang,
  • Sojung Park,
  • Eunji Kim,
  • Seak Hee Oh,
  • Inki Kim

摘要

Background

Resistance to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a main limitation in breast cancer therapy. Identifying effective sensitizers is crucial to overcome this hurdle. Cyclin-dependent kinase-9 (CDK-9) inhibition has recently emerged as a potential strategy to enhance apoptotic responses in cancer cells.

Materials and methods

We investigated the effect of A09-003, a novel CDK9 inhibitor, on TRAIL-induced apoptosis and cell signaling in TNBC breast cancer cells. Cell viability was assessed by CellTiter-Glo assays, while apoptotic induction was evaluated using Flow cytometry analysis with Annexin V/PI staining, DNA fragmentation, and caspase activity assay. Protein expression levels of Mcl-1 and death receptors were analyzed via Western blotting and real time PCR. Mechanistic studies explored Mcl-1 protein degradation and transcriptional regulation through CDK-9 inhibition.

Results

A09-003 significantly enhanced TRAIL-induced apoptosis in tested breast cancer cells by increasing death receptor 5 expression, promoting caspase activation, and DNA fragmentation. Mechanistically, A09-003 downregulated Mcl-1 expression through dual pathways: promoting its proteasomal degradation and suppressing transcription via inhibition of CDK9-dependent RNA polymerase II phosphorylation.

Conclusion

A09-003 restores TRAIL sensitivity through Mcl-1 downregulation, identifying CDK-9 as a therapeutic target in resistant breast cancers.