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

Molecular Cancer

Research

Giovanna Chiorino¹  Barbara Pasini²  Francesca Vignolo Lutati²  Annalisa Lorenzato³  Dario Sangiolo⁴  Lucia Napione⁵  Massimo Aglietta⁶  Maria Serena Benassi⁷  Loretta Gammaitoni⁸  Marco Basiricò⁹  Carmine Dell’Aglio^1,10  Giovanni Grignani^1,11  Sandra Aliberti^1,11  Giulia Chiabotto^1,11  Sara Miano^1,12  Erica Palesandro^1,12  Paola Boccone^1,12  Lorenzo D’Ambrosio^1,12  Danilo Galizia^1,12  Ymera Pignochino^1,12  Federica Capozzi^1,12  Marta Canta^1,12 

[1] Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, Biella, Italy;Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy;Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy;Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy;Laboratory of Vascular Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy;Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy;Laboratory of Vascular Oncology, Candiolo Cancer Institute – FPO, IRCCS, Candiolo, Torino, Italy;Current address: Department of Applied Science and Technology, Politecnico di Torino, Torino, Italy;Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy;Medical Oncology, Candiolo Cancer Institute – FPO, IRCCS, Candiolo, Torino, Italy;Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy;Laboratory of Vascular Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy;Medical Oncology, Candiolo Cancer Institute – FPO, IRCCS, Candiolo, Torino, Italy;Pathology Unit, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy;Sarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy;Sarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy;Department of Oncology, University of Torino Medical School, Candiolo, Torino, Italy;

关键词: Predictive biomarkers;    PARP1 inhibitors;    DNA-damaging agents;    Trabectedin;    Olaparib;    Bone and soft tissue sarcomas;    Drug synergism;   

DOI  :  10.1186/s12943-017-0652-5

 received in 2016-07-01, accepted in 2017-04-17,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundEnhancing 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.MethodsWe 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.ResultsTrabectedin 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.ConclusionsPARP1 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.

【 授权许可】

CC BY   
© The Author(s). 2017