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

James E Melnyk; Veronica Steri; Hao G Nguyen; Byron Hann; Felix Y Feng; Kevan M Shokat

doi:10.1016/j.bmc.2020.115712

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. Epub 2020 Aug 18.

Authors

James E Melnyk¹, Veronica Steri², Hao G Nguyen³, Byron Hann², Felix Y Feng⁴, Kevan M Shokat⁵

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: kevan.shokat@ucsf.edu.

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.

Publication types

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

MeSH terms

Alternative Splicing / drug effects
Alternative Splicing / genetics
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
RNA, Messenger / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Tumor Cells, Cultured

Substances

AR protein, human
Antineoplastic Agents
N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
RNA, Messenger
Receptors, Androgen
Sulfonamides

Abstract

Publication types

MeSH terms

Substances

Grants and funding