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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

Authors: Ymera Pignochino, Federica Capozzi, Lorenzo D’Ambrosio, Carmine Dell’Aglio, Marco Basiricò, Marta Canta, Annalisa Lorenzato, Francesca Vignolo Lutati, Sandra Aliberti, Erica Palesandro, Paola Boccone, Danilo Galizia, Sara Miano, Giulia Chiabotto, Lucia Napione, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Barbara Pasini, Giovanna Chiorino, Massimo Aglietta, Giovanni Grignani

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.

Methods

We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.

Results

Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.

Conclusions

PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
Appendix
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Metadata
Title
PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
Authors
Ymera Pignochino
Federica Capozzi
Lorenzo D’Ambrosio
Carmine Dell’Aglio
Marco Basiricò
Marta Canta
Annalisa Lorenzato
Francesca Vignolo Lutati
Sandra Aliberti
Erica Palesandro
Paola Boccone
Danilo Galizia
Sara Miano
Giulia Chiabotto
Lucia Napione
Loretta Gammaitoni
Dario Sangiolo
Maria Serena Benassi
Barbara Pasini
Giovanna Chiorino
Massimo Aglietta
Giovanni Grignani
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0652-5

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