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The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells

James E Melnyk1, Veronica Steri2, Hao G Nguyen3

  • 1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

Bioorganic & Medicinal Chemistry
|October 17, 2020
PubMed

Insights

The splicing factor RBM39 drives androgen receptor variant 7 (AR-V7) in prostate cancer. The drug indisulam degrades RBM39, reducing AR-V7 mRNA and offering a potential therapeutic strategy for castration resistant prostate cancer (CRPC).

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Alternative splicing of the androgen receptor (AR) is prevalent in castration resistant prostate cancer (CRPC).
  • The AR-V7 splice variant is a constitutively active, undruggable transcription factor linked to resistance against androgen receptor signaling inhibitors (ARSi) and poor prognoses.
  • Mechanisms driving AR-V7 expression via spliceosome activity on AR pre-mRNA are not fully understood.

Purpose of the Study:

  • To elucidate the mechanistic details of AR-V7 splice variant formation.
  • To identify key splicing factors involved in AR-V7 generation.
  • To evaluate the therapeutic potential of targeting the AR-V7 splicing pathway.

Main Methods:

  • Investigated the role of splicing factor RBM39 in AR-V7 alternative splicing.
  • Assessed the impact of the anti-cancer drug indisulam on RBM39 and AR-V7 mRNA levels.
  • Utilized in vitro and in vivo models to validate findings.

Main Results:

  • Demonstrated that splicing factor RBM39 is critical for AR-V7 alternative splicing.
  • Showed that indisulam reduces AR-V7 mRNA levels by inducing RBM39 degradation.
  • Confirmed that indisulam effectively reduces AR-V7 in both in vitro and in vivo experimental settings.

Conclusions:

  • RBM39 is a key driver of AR-V7 splice variant formation in CRPC.
  • Indisulam effectively targets RBM39, leading to decreased AR-V7 expression.
  • Indisulam represents a promising therapeutic agent for CRPC by inhibiting AR-V7 production.
Keywords:
AR-V7Alternative splicingAndrogen receptorIndisulamProstate cancerRBM39

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