PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

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 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)