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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models

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Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed

Bo Cao1, Yanfeng Qi, Guanyi Zhang

  • 1Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA.

Oncotarget
|April 12, 2014
PubMed

Insights

Androgen receptor splice variants (AR-Vs) promote castration-resistant prostate cancer by enabling androgen receptor nuclear localization and reducing enzalutamide effectiveness, impacting treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Constitutively-active androgen receptor splice variants (AR-Vs) are linked to prostate cancer progression.
  • Previous research focused on AR-Vs' independent gene regulation, not their interaction with full-length AR (AR-FL).

Purpose of the Study:

  • To investigate the functional role of AR-Vs, specifically AR-V7 and ARv567es, in the context of androgen receptor signaling and enzalutamide resistance.
  • To elucidate the mechanisms by which AR-Vs influence AR-FL activity and therapeutic response.

Main Methods:

  • Investigated AR-V7 and ARv567es effects on AR-FL nuclear localization.
  • Assessed AR-V/AR-FL co-occupancy at target gene promoters.
  • Evaluated the impact of AR-V expression on androgen and enzalutamide modulation of AR-FL activity.
  • Monitored ARv567es levels in enzalutamide-resistant xenograft models.

Main Results:

  • AR-V7 and ARv567es facilitate AR-FL nuclear localization independently of androgen.
  • AR-Vs mitigate enzalutamide's inhibition of AR-FL nuclear trafficking.
  • AR-Vs bind to specific target promoters alone and co-occupy canonical AR targets with AR-FL.
  • AR-V expression reduces the efficacy of both androgen and enzalutamide treatments and diminishes enzalutamide's in vivo antitumor activity.
  • ARv567es levels increase in xenografts resistant to enzalutamide.

Conclusions:

  • AR-Vs play a dual role in castration resistance, acting both independently and by modulating AR-FL.
  • AR-Vs function as a rheostat, controlling AR-FL response to therapy by promoting androgen-independent activation.
  • Findings offer new insights into AR-V-mediated castration resistance mechanisms and potential therapeutic strategies.

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