Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.
Irene FischettiLaura BottiRoberta SulsentiValeria CancilaClaudia EnriquezRenata FerriMarco BregniFilippo CrivelliClaudio TripodoMario P ColomboElena JachettiPublished in: Epigenomics (2024)
Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8 + T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.
Keyphrases
- prostate cancer
- radical prostatectomy
- signaling pathway
- pi k akt
- mouse model
- dna methylation
- gene expression
- long non coding rna
- immune response
- emergency department
- type diabetes
- long noncoding rna
- mass spectrometry
- high fat diet induced
- atomic force microscopy
- cancer therapy
- cell proliferation
- high resolution
- insulin resistance
- drug delivery
- electronic health record
- smoking cessation
- anti inflammatory