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Transient splicing inhibition causes persistent DNA damage and chemotherapy vulnerability in triple-negative breast

Cinzia Caggiano1, Valerio Petrera2, Miriana Ferri2

  • 1Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; GSTeP Organoids Research Core Facility, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 00168 Rome, Italy.

Cell Reports
|September 14, 2024
PubMed

Insights

Targeting the U2 small nuclear ribonucleoprotein particle (snRNP) complex can overcome chemotherapy resistance in triple negative breast cancer (TNBC). Inhibiting U2 snRNP causes DNA damage and enhances drug effectiveness in TNBC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Triple negative breast cancer (TNBC) is an aggressive subtype known for initial chemotherapy sensitivity but frequent acquired resistance.
  • Acquired resistance leads to disease progression and poorer patient outcomes, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

  • To identify novel targets that modulate chemotherapy efficacy in triple negative breast cancer.
  • To investigate the role of the spliceosome U2 small nuclear ribonucleoprotein particle (snRNP) complex in chemotherapy resistance.

Main Methods:

  • Utilized TNBC cell lines and organoids to assess the impact of transient U2 snRNP inhibition.
  • Analyzed DNA damage response (DDR) gene deregulation and protein expression following splicing inhibition.
  • Evaluated the combined cytotoxic effects of U2 snRNP inhibition with platinum-based drugs and PARP inhibitors.

Main Results:

  • Transient U2 snRNP inhibition induced persistent DNA damage in TNBC cells and organoids, irrespective of homologous recombination proficiency.
  • U2 snRNP inhibition led to widespread deregulation of DDR genes, particularly those with small exons.
  • Splicing inhibition resulted in sustained repression of DDR proteins and potentiated the cytotoxicity of platinum drugs and PARP inhibitors.

Conclusions:

  • The U2 snRNP complex is a key modulator of chemotherapy efficacy in triple negative breast cancer.
  • Targeting U2 snRNP represents a promising strategy to enhance the effectiveness of current chemotherapies in TNBC.
  • Exploiting U2 snRNP offers a novel therapeutic avenue for overcoming treatment resistance in aggressive breast cancers.
Keywords:
CP: CancerDNA damagecombined treatmenthomologous recombinationpladienolide Bsplicing inhibitorstargeted therapytriple negative breast cancer

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