Transient splicing inhibition causes persistent DNA damage and chemotherapy vulnerability in triple-negative breast cancer
Cinzia Caggiano,
Valerio Petrera,
Miriana Ferri,
Marco Pieraccioli,
Eleonora Cesari,
Alba Di Leone,
Martin Alejandro Sanchez,
Alessandra Fabi,
Riccardo Masetti,
Chiara Naro,
Claudio Sette
Affiliations
Cinzia Caggiano
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; Corresponding author
Valerio Petrera
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
Miriana Ferri
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
Marco Pieraccioli
GSTeP Organoids Research Core Facility, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 00168 Rome, Italy
Eleonora Cesari
GSTeP Organoids Research Core Facility, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 00168 Rome, Italy
Alba Di Leone
Breast Unit, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
Martin Alejandro Sanchez
Breast Unit, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
Alessandra Fabi
Breast Unit, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
Riccardo Masetti
Breast Unit, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
Chiara Naro
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
Claudio Sette
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; Corresponding author
Summary: 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.
