title: PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma.
abstract: Ewing's sarcoma family of tumors (ESFT) refers to aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here, we report that these fusion products interact with the DNA damage response protein and transcriptional coregulator PARP-1. ESFT cells, primary tumor xenografts, and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong preclinical rationale to target the EWS-FLI1:PARP1 intersection as a therapeutic strategy to improve the treatment of ESFTs.
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Sumin
authors.initials: S
authors.lastname: Han
authors.forename: Sonam
authors.initials: S
authors.lastname: Patel
authors.forename: Siddharth V
authors.initials: SV
authors.lastname: Goyal
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bou-Maroun
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Lonigro
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000502:physiology; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000502:physiology; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib