Abstract
Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
Highlights
Ewing Sarcoma (ES) is an aggressive developmental mesenchymal tumor [1]
We observed that ES cell lines previously described as 1qG showed an amplification of poly (ADP-ribose) polymerase-1 (PARP1) by fluorescence in situ hybridization (FISH) (Figure 1A). cDNA analysis showed that all ES cell lines express PARP1 with different mRNA levels (Figure 1B)
We studied the sensitivity of ES cell lines to a group of PARP inhibitors (PARPinh), including Olaparib, Veliparib and Iniparib
Summary
ES is an aggressive developmental mesenchymal tumor [1]. As a result of multimodal therapy, including strategies from traditional chemotherapeutic agents, radiotherapy, and surgery, the current cure rate of ES patients with localized disease is 70% [2, 3]. We report that the combination of Trabectedin and Olaparib is highly synergistic in ES cell lines, inducing major DNA damage in vitro and in vivo and causing a clinically significant degree of tumor regression in PDX) models of ES. We observed that the drug combination (250pM of Trabectedin and 5μM of Olaparib) increased the apoptotic rate in the TC71 cell line (Supplementary Figure S2A).
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