Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer.
Yukiyoshi HirayamaTeresa TamKunzhong JianRaymond J AndersenMarianne D SadarPublished in: Molecular oncology (2020)
Resistance of castration-resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD. Here, we evaluated the antitumor effect of a next-generation analog of ralaniten (EPI-7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR-V7 that were resistant to enzalutamide. EPI-7170 had 8-9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR-V7 and expression of its target genes. Knockdown of AR-V7 restored sensitivity to enzalutamide, indicating a role for AR-V7 in the mechanism of resistance. EPI-7170 inhibited expression of genes transcriptionally regulated by full-length AR and AR-V7. A combination of EPI-7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide-resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.
Keyphrases
- prostate cancer
- combination therapy
- radical prostatectomy
- cell cycle
- poor prognosis
- emergency department
- cell proliferation
- risk assessment
- randomized controlled trial
- dna methylation
- gene expression
- drug delivery
- clinical trial
- binding protein
- mesenchymal stem cells
- cell therapy
- stem cells
- cell death
- cancer therapy
- bone marrow
- genome wide
- electronic health record
- climate change
- adverse drug
- heat stress