Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1

  • Oncogene. 2022 Mar;41(11):1536-1549. doi: 10.1038/s41388-022-02179-z.
James E Melnyk  1 ,  Veronica Steri  2  3 ,  Hao G Nguyen  2  4 ,  Y Christina Hwang  2  5 ,  John D Gordan  2  5 ,  Byron Hann  2  3 ,  Felix Y Feng  2  4  6  7 ,  Kevan M Shokat  8  9
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.
  • 3. Preclinical Therapeutics Core, University of California San Francisco, San Francisco, CA, 94158, USA.
  • 4. Department of Urology, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 5. Department of Medicine and Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, 94158, USA.
  • 6. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 7. Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 8. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, 94158, USA. [email protected].
  • 9. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, 94143, USA. [email protected].
PMID: 35087237 DOI: 10.1038/s41388-022-02179-z
Abstract

The Androgen Receptor (AR) is a central driver of aggressive prostate Cancer. After initial treatment with Androgen Receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where Hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ Inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate Cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate Cancer.

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