Abstract 30P
Background
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a high incidence of tumour recurrence. Although radiotherapy remains a key treatment modality, acquired radioresistance remains a major challenge in disease management. To enhance treatment efficacy for TNBC patients, identifying novel and effective radiosensitizing agents is critical. This study investigates histone deacetylase inhibitors (HDACi) as epigenetic modulators to sensitize radioresistant TNBC cells and explores underlying mechanism of the radioresistance.
Methods
TNBC radiation-resistant clones (RR) were derived from parent cells by simulating a clinical fractionated radiation dose of 40 Gray. The RR cells were characterized using colony-forming, migration assay and FACS analysis. Various FDA-approved HDAC inhibitors were screened for their radiosensitizing potential in RR cells. Mechanistic insights into radioresistance were obtained through gene expression analysis using qRT-PCR.
Results
RR cells demonstrated radiation resistance, formed larger colonies, and exhibited higher proliferation and migration rates compared to parent cells. Among the tested HDACi (Romidespin, SAHA, and Belinostat), Romidepsin showed most promising cytotoxic effects in RR cells. However, its efficacy was reduced in RR cells compared to parent cells. Gene expression analysis revealed upregulation of cancer stemness markers (OCT4, SOX2, NANOG), epithelial mesenchymal transition markers (N-Cad, Fibronectin and ZEB1), and ABC efflux transporters (ABCC1, ABCC2 and ABCG2) in the resistant clones. Further, pre-treatment with verapamil, an ABC transporter efflux pump inhibitor, reduced Hoechst dye efflux in RR-cells. Importantly, verapamil resensitized RR-cells to Romidepsin, suggesting efflux transporters might contribute to the reduced efficacy of HDCAi in RR cells.
Conclusions
Combining Romidepsin with Verapamil synergistically enhanced cytotoxicity of radiation resistant TNBC cells. This study highlights the potential of combining ABC transporter efflux inhibitors with HDACi as a promising therapeutic strategy to overcome radiation resistance and improve treatment outcomes for TNBC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Board of Research in Nuclear Sciences (BRNS).
Disclosure
All authors have declared no conflicts of interest.