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Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1
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Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1
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Journal Article
Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1
2022
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/39
/ 38/77
/ Androgen Antagonists - pharmacology
/ Androgen Antagonists - therapeutic use
/ Gene Expression Regulation, Neoplastic
/ Genomics
/ Humans
/ Male
/ Medicine
/ Oncology
/ Prostatic Neoplasms - drug therapy
/ Prostatic Neoplasms - genetics
/ Prostatic Neoplasms - metabolism
/ Prostatic Neoplasms, Castration-Resistant - genetics
/ Protein Kinase C beta - metabolism
/ Receptors, Androgen - genetics
