Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer

Clin Cancer Res. 2016 Jun 1;22(11):2744-54. doi: 10.1158/1078-0432.CCR-15-2119. Epub 2015 Dec 28.

Abstract

Purpose: The PI3K/Akt/mTOR pathway is activated in most castration-resistant prostate cancers (CRPC). Transcriptionally active androgen receptor (AR) plays a role in the majority of CRPCs. Therefore, cotargeting full-length (FL) AR and PI3K/Akt/mTOR signaling has been proposed as a possible, more effective therapeutic approach for CRPC. However, truncated AR-splice variants (AR-V) that are constitutively active and dominant over FL-AR are associated with tumor progression and resistance mechanisms in CRPC. It is currently unknown how blocking the PI3K/Akt/mTOR pathway impacts prostate cancer driven by AR-Vs. Here, we evaluated the efficacy and mechanism of combination therapy to block mTOR activity together with EPI-002, an AR N-terminal domain (NTD) antagonist that blocks the transcriptional activities of FL-AR and AR-Vs in models of CRPC.

Experimental design: To determine the functional roles of FL-AR, AR-Vs, and PI3K/Akt/mTOR pathways, we employed EPI-002 or enzalutamide and BEZ235 (low dose) or everolimus in human prostate cancer cells that express FL-AR or FL-AR and AR-Vs (LNCaP95). Gene expression and efficacy were examined in vitro and in vivo

Results: EPI-002 had antitumor activity in enzalutamide-resistant LNCaP95 cells that was associated with decreased expression of AR-V target genes (e.g., UBE2C). Inhibition of mTOR provided additional blockade of UBE2C expression. A combination of EPI-002 and BEZ235 decreased the growth of LNCaP95 cells in vitro and in vivo

Conclusions: Cotargeting mTOR and AR-NTD to block transcriptional activities of FL-AR and AR-Vs provided maximum antitumor efficacy in PTEN-null, enzalutamide-resistant CRPC. Clin Cancer Res; 22(11); 2744-54. ©2015 AACR.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzhydryl Compounds / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Everolimus / administration & dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycerol / analogs & derivatives*
  • Glycerol / pharmacology
  • Imidazoles / administration & dosage
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenylthiohydantoin / administration & dosage
  • Phenylthiohydantoin / analogs & derivatives
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Quinolines / administration & dosage
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Hormonal
  • Benzhydryl Compounds
  • EPI-002
  • Imidazoles
  • MDV 3100
  • Protein Isoforms
  • Quinolines
  • Receptors, Androgen
  • Phenylthiohydantoin
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Glycerol
  • dactolisib