2. Academic Validation
  3. Transient splicing inhibition causes persistent DNA damage and chemotherapy vulnerability in triple-negative breast cancer

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

  • Cell Rep. 2024 Sep 24;43(9):114751. doi: 10.1016/j.celrep.2024.114751.
Cinzia Caggiano 1,  Valerio Petrera 2,  Miriana Ferri 2,  Marco Pieraccioli 3,  Eleonora Cesari 3,  Alba Di Leone 4,  Martin Alejandro Sanchez 4,  Alessandra Fabi 4,  Riccardo Masetti 4,  Chiara Naro 5,  Claudio Sette 6
Affiliations

Affiliations

  • 1 Department 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. Electronic address: cinzia.caggiano@unicatt.it.
  • 2 Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy.
  • 3 GSTeP Organoids Research Core Facility, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 00168 Rome, Italy.
  • 4 Breast Unit, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy.
  • 5 Department 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.
  • 6 Department 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. Electronic address: claudio.sette@unicatt.it.
PMID: 39276346 DOI: 10.1016/j.celrep.2024.114751
Abstract

Triple negative breast Cancer (TNBC) is an aggressive type of breast Cancer. While most TNBCs are initially sensitive to chemotherapy, a substantial fraction acquires resistance to treatments and progresses to more advanced stages. Here, we identify the spliceosome U2 small nuclear ribonucleoprotein particle (snRNP) complex as a modulator of chemotherapy efficacy in TNBC. Transient U2 snRNP inhibition induces persistent DNA damage in TNBC cells and organoids, regardless of their homologous recombination proficiency. U2 snRNP inhibition pervasively deregulates genes involved in the DNA damage response (DDR), an effect relying on their genomic structure characterized by a high number of small exons. Furthermore, a pulse of splicing inhibition elicits long-lasting repression of DDR proteins and enhances the cytotoxic effect of platinum-based drugs and poly(ADP-ribose) polymerase inhibitors (PARPis) in multiple TNBC models. These findings identify the U2 snRNP as an actionable target that can be exploited to enhance chemotherapy efficacy in TNBCs.

Keywords

CP: Cancer; DNA damage; combined treatment; homologous recombination; pladienolide B; splicing inhibitors; targeted therapy; triple negative breast cancer.

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