Trabectedin efficacy in Ewing sarcoma is greatly increased by combination with anti-IGF signaling agents
Menée sur des lignées cellulaires de sarcome d'Ewing et à l'aide de xénogreffes, cette étude met en évidence des mécanismes suggérant l'intérêt d'un traitement combinant la trabectédine avec des agents anti-IGF-1R
Purpose: Goal of this study was to identify mechanisms that limit efficacy of trabectedin (ET-743, YondelisTM) in Ewing sarcoma (EWS), so as to develop a clinical applicable combination therapy. Experimental Design: By chromatin immunoprecipitation, we analyzed EWS-FLI1 binding to the promoters of several target genes such as TGFβR2, CD99, insulin-like growth factor receptor 1 (IGF-1R), and IGF-1 both in vitro and in xenografts treated with trabectedin or doxorubicin. Combined therapy with trabectedin and anti-IGF-1R agents (AVE1642 HAb; OSI-906) was tested in vitro and in xenografts. Results: We confirm that both trabectedin and doxorubicin were able to strongly reduce EWS-FLI1 (both type 1 and type 2) binding to two representative target genes (TGFβR2 and CD99), both in vitro and in xenografts. However, trabectedin but not doxorubicin was also able to increase the occupancy of EWS-FLI1 to IGF-1R promoters, leading to IGF-1R up-regulation. Inhibition of IGF-1R either by the specific AVE1642 human antibody or by the dual IGF-1R/Insulin receptor inhibitor OSI-906 (Linsitinib) greatly potentiate the efficacy of trabectedin in the 13 Ewing sarcoma cell lines here considered as well as in TC-71 and 6647 xenografts. Combined therapy induced synergistic cytotoxic effects. Trabectedin and OSI-906 deliver complementary messages that likely converge on DNA damage response and repair pathways. Conclusions: We showed that trabectedin may not only inhibit but also enhance thebinding of EWS-FLI1 to certain target genes, leading to up-regulation of IGF-1R. We here provide the rationale for combining trabectedin to anti-IGF-1R inhibitors.