Reversing Bladder Cancer Chemo-resistance through Blocking Cell Senescence by a Combination Therapy.

RATIONALE: Chemoresistance severely limits therapeutic options for advanced bladder cancer. Histone deacetylases (HDACs) have been implicated in tumour progression and treatment resistance, yet their role in acquired chemoresistance remains incompletely defined. We investigated whether epigenetic modulation could restore chemotherapy sensitivity in drug-refractory bladder cancer.

METHODS

Expression of HDAC1-3 was analysed in tumour tissues and correlated with clinical outcomes and chemoresistance-associated transcriptional programmes. A co-delivery therapeutic strategy combining the pan-HDAC inhibitor belinostat (PXD101) with paclitaxel (PTX) was developed and evaluated in patient-derived cisplatin-resistant organoids and a platinum-refractory patient-derived xenograft (PDX) model. Functional assays and genetic perturbation experiments were performed to delineate the underlying mechanisms.

RESULTS

HDAC1-3 were upregulated in bladder cancer tissues and associated with adverse prognosis and chemoresistance signatures. Combined PXD101 and PTX treatment significantly suppressed tumour growth in organoids and PDX models, with improved tolerability compared with standard regimens. Mechanistically, PXD101 attenuated senescence-associated programmes and reduced CDKN1A/p21 expression, thereby restoring PTX-induced antimitotic activity. Genetic manipulation identified p21 as a molecular switch linking therapy-induced senescence to chemoresistance. Modulation of p21 influenced cell-cycle re-entry, senescence burden, and responsiveness to PTX.

CONCLUSIONS

These findings define an HDAC-p21-senescence axis that sustains chemoresistance in bladder cancer and provide preclinical evidence supporting combined epigenetic and antimitotic therapy as a strategy to overcome acquired drug tolerance.