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| Status |
Public on Jun 12, 2017 |
| Title |
PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
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| Summary |
Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response
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| Overall design |
A first panel of bone and soft tissue sarcoma cell lines were analyzed in terms of response and sensitivity to trabectedin and olaparib combination. A group of cells displaying high synergism of the combination was then compared with a group of cells with low synergism of the combination. Validation of PARP1 role was then performed in a second panel of non sarcoma cells ( mesotheliomas, colon breast, prostate, cholangio and lung carcinomas)
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| Contributor(s) |
Pignochino Y, Capozzi F, D'Ambrosio L, Dell'Aglio C, Basiricò M, Canta M, Aliberti S, Palesandro E, Boccone P, Ostano P, Gregnanin I, Galizia D, Gammaitoni L, Sangiolo D, Lorenzato A, Lutati FV, Benassi MS, Chiorino G, Pasini B, Aglietta M, Grignani G |
| Citation(s) |
28454547 |
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| Submission date |
Jan 25, 2016 |
| Last update date |
Jun 12, 2017 |
| Contact name |
giovanna chiorino |
| E-mail(s) |
giovanna.chiorino@gmail.com
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| Organization name |
Fondo Edo Tempia
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| Department |
Cancer Genomics
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| Street address |
via malta 3
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| City |
Biella |
| ZIP/Postal code |
13900 |
| Country |
Italy |
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| Platforms (1) |
| GPL16237 |
Agilent-030587 CCMC CGH plus SNP 180k Microarray |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA309661 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE77175_RAW.tar |
396.4 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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