title: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.
abstract: Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, 1400 E. Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Anastasia K
authors.initials: AK
authors.lastname: Yocum
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Sonam
authors.initials: S
authors.lastname: Patel
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Wang
authors.forename: Hallie
authors.initials: H
authors.lastname: Liang
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Javed
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authors.lastname: Siddiqui
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Aaron
authors.initials: A
authors.lastname: Sabolch
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011487:Protein Conformation; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011993:Recombinant Fusion Proteins; C515553:TMPRSS2-ERG fusion protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; C531550:olaparib