NF-κB Blockade with Oral Administration of Dimethylaminoparthenolide (DMAPT), Delays Prostate Cancer Resistance to Androgen Receptor (AR) Inhibition and Inhibits AR Variants
Abstract
NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB–driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies, including decrease of NF-κB in circulating leuchemic blasts. Here, we report that activation of NF-κB/p65 by castration in mouse and human prostate cancer models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT-sensitizing prostate cancer cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 16, 2021
- Source ID
- 10.1158/1541-7786.mcr-21-0099
Entities
People
- Anis A Hamid
- Christopher Sweeney
- John G Clohessy
- Katherine L Morel
- Leigh Ellis
- Nicole Pandell
Organizations
- Dana–Farber Cancer Institute
- Harvard Medical School
- United States Department of Defense