|
| Status |
Public on Jun 12, 2017 |
| Title |
PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| 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.
|
| |
|
| Overall design |
six bone and soft tissue sarcoma cell lines treated with trabectedin, olaparib and combination
|
| |
|
| Contributor(s) |
Pignochino Y, Grignani G |
| Citation(s) |
28454547 |
| |
| Submission date |
Jan 19, 2016 |
| Last update date |
Aug 13, 2018 |
| Contact name |
ymera pignochino |
| E-mail(s) |
ymera.pignochino@ircc.it
|
| Organization name |
IRCCS Candiolo cancer center
|
| Street address |
str provinciale 142
|
| City |
Candiolo |
| ZIP/Postal code |
10060 |
| Country |
Italy |
| |
|
| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
|
| Samples (24)
|
|
| Relations |
| BioProject |
PRJNA309170 |
Less...
More...