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

  • Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712.
James E Melnyk  1 ,  Veronica Steri  2 ,  Hao G Nguyen  3 ,  Byron Hann  2 ,  Felix Y Feng  4 ,  Kevan M Shokat  5
Affiliations
  • 1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Preclinical Therapeutics Core, University of California San Francisco, San Francisco, CA 94158, USA.
  • 3. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 33069070 DOI: 10.1016/j.bmc.2020.115712
Abstract

Alternative splicing of the Androgen Receptor (AR) is frequently observed in castration resistant prostate Cancer (CRPC). One AR isoform, the AR-V7 splice variant, is a constitutively active transcription factor which lacks a ligand binding domain and is therefore undruggable. AR-V7 expression correlates with resistance to Androgen Receptor signaling inhibitors (ARSi) and poor clinical prognoses. The occurrence of the AR-V7 splice variant is driven by alternative splicing of AR pre-mRNA by the spliceosome, however the mechanistic details are poorly understood. We demonstrate that the splicing factor RBM39 is critical for alternative splicing of the AR-V7 splice variant mRNA transcripts from AR pre-mRNA, and that the anti-cancer drug, indisulam, reduces AR-V7 mRNA levels by degrading RBM39. We report that indisulam effectively reduces AR-V7 in in vitro and in vivo models.

Keywords
AR-V7; Alternative splicing; Androgen receptor; Indisulam; Prostate cancer; RBM39.
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