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Updated: Jul 2, 2025

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer

Chiara Naro1,2, Ambra Antonioni1, Vanessa Medici1

  • 1Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168, Rome, Italy.

Journal of Experimental & Clinical Cancer Research : CR
|February 27, 2024
PubMed
Abstract

Insights

Splicing dysregulation drives advanced prostate cancer (PC). Targeting intron retention with specific drugs, like Pladienolide B, indisulam, and THZ531, shows promise for treating this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Advanced prostate cancer (PC) is resistant to current therapies, necessitating novel treatment strategies.
  • Splicing dysregulation is a key feature of advanced PC.
  • Pharmacologic inhibition of splicing presents a promising therapeutic avenue for advanced PC.

Purpose of the Study:

  • To investigate the transcriptomic effects of splicing-targeting drugs (Pladienolide B, indisulam, THZ531) in advanced PC.
  • To identify gene structural features associated with sensitivity to splicing-targeting drugs.
  • To explore the therapeutic potential of targeting splicing in advanced PC.

Main Methods:

  • Utilized an androgen-insensitive PC cell line (22Rv1) for genome-wide transcriptomic analysis.
  • Applied bioinformatic and gene ontology analyses to understand drug-induced splicing alterations.
  • Validated findings through functional experiments in cell models.

Main Results:

  • Splicing-targeting drugs induce distinct transcriptomic and splicing signatures, impacting cell survival.
  • Drug sensitivity correlates with specific gene structures, expression levels, and sequence elements.
  • Identified intron retention as a widespread effect, particularly in genes involved in pre-mRNA 3'-end processing, and demonstrated sensitivity to cleavage and polyadenylation complex inhibitors.

Conclusions:

  • Intron retention is a targetable vulnerability in advanced prostate cancer.
  • Splicing-targeting drugs can be leveraged to enhance the efficacy of existing chemotherapies.
  • This research offers a new therapeutic strategy for advanced PC, improving patient outcomes.
Keywords:
3’-end mRNA processingAdvanced prostate cancerAlternative splicingIntron-retentionSplicing inhibitorsTranscriptomics

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