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Background <p>Chemotherapy remains the most preferred therapeutic option for Triple-Negative breast cancer (TNBC), but patients frequently develop resistance over time, which remains a major clinical challenge, leading to poor patient treatment outcomes.</p> Methods <p>We established Cisplatin-resistant MDA-MB-231 cells. Cell viability and drug response were evaluated via the MTT and SRB assays. Colony formation and migration assays were conducted to assess clonogenic and metastatic capabilities. A comprehensive bioinformatics analysis was performed to identify differentially expressed genes. Protein expression and localisation analysis was conducted through western blotting and immunofluorescence. Functional validation was performed using siRNA-mediated knockdown, and protein interactions were evaluated by co-immunoprecipitation (Co-IP). In vivo studies assessed the therapeutic efficacy of TNKS inhibition with XAV-939 alone and in combination with cisplatin.</p> Results <p>The study demonstrates that TFEB regulates the expression of the multidrug efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2), a crucial factor in drug resistance mechanisms. The nuclear translocation of TFEB is demonstrated to rely on TNKS-mediated PARsylation, a post-translational modification that enhances its entry into the nucleus from the cytoplasm. Upon entering the nucleus, TFEB interacts with β-catenin to initiate the transcriptional activation of ABCG2. The pharmacological inhibition of TNKS via the utilisation of XAV-939 interferes with the trafficking of TFEB that is dependent on PARsylation, leading to a reduction in ABCG2 expression and thus compromised cisplatin efflux capability of CR cells.The in vivo studies validated the reduction in tumour growth following TNKS blockade, either alone or in conjunction with cisplatin.</p> Conclusion <p>Targeting TNKS represents a potentially effective therapeutic approach to address cisplatin resistance and improve treatment outcomes in TNBC.</p> Graphical Abstract <p>This figure illustrates the role of TNKS and its inhibition in Resistant cancer cells</p>

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Tankyrase inhibition restores chemosensitivity in triple-negative breast cancer cells by disrupting TFEB/β-Catenin/ABCG2 axis

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Shariqa Jan,
  • Kaneez Fatima,
  • Sameer Ullah Khan,
  • Fayaz A. Malik

摘要

Background

Chemotherapy remains the most preferred therapeutic option for Triple-Negative breast cancer (TNBC), but patients frequently develop resistance over time, which remains a major clinical challenge, leading to poor patient treatment outcomes.

Methods

We established Cisplatin-resistant MDA-MB-231 cells. Cell viability and drug response were evaluated via the MTT and SRB assays. Colony formation and migration assays were conducted to assess clonogenic and metastatic capabilities. A comprehensive bioinformatics analysis was performed to identify differentially expressed genes. Protein expression and localisation analysis was conducted through western blotting and immunofluorescence. Functional validation was performed using siRNA-mediated knockdown, and protein interactions were evaluated by co-immunoprecipitation (Co-IP). In vivo studies assessed the therapeutic efficacy of TNKS inhibition with XAV-939 alone and in combination with cisplatin.

Results

The study demonstrates that TFEB regulates the expression of the multidrug efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2), a crucial factor in drug resistance mechanisms. The nuclear translocation of TFEB is demonstrated to rely on TNKS-mediated PARsylation, a post-translational modification that enhances its entry into the nucleus from the cytoplasm. Upon entering the nucleus, TFEB interacts with β-catenin to initiate the transcriptional activation of ABCG2. The pharmacological inhibition of TNKS via the utilisation of XAV-939 interferes with the trafficking of TFEB that is dependent on PARsylation, leading to a reduction in ABCG2 expression and thus compromised cisplatin efflux capability of CR cells.The in vivo studies validated the reduction in tumour growth following TNKS blockade, either alone or in conjunction with cisplatin.

Conclusion

Targeting TNKS represents a potentially effective therapeutic approach to address cisplatin resistance and improve treatment outcomes in TNBC.

Graphical Abstract

This figure illustrates the role of TNKS and its inhibition in Resistant cancer cells