title: Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors.
abstract: When the integrity of the genome is threatened, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extent of damage is beyond repair capacity, induce apoptotic cell death. The ATM protein lies at the heart of this signaling network, which is collectively referred to as the DNA damage response (DDR). ATM is involved in numerous DDR-regulated cellular responses-cell cycle arrest, DNA repair, and apoptosis. Disabling mutations in the gene encoding ATM occur frequently in various human tumors, including lung cancer and hematological malignancies. We report that ATM deficiency prevents apoptosis in human and murine cancer cells exposed to genotoxic chemotherapy. Using genetic and pharmacological approaches, we demonstrate in vitro and in vivo that ATM-defective cells display strong non-oncogene addiction to DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Further, this dependence of ATM-defective cells on DNA-PKcs offers a window of opportunity for therapeutic intervention: We show that pharmacological or genetic abrogation of DNA-PKcs in ATM-defective cells leads to the accumulation of DNA double-strand breaks and the subsequent CtBP-interacting protein (CtIP)-dependent generation of large single-stranded DNA (ssDNA) repair intermediates. These ssDNA structures trigger proapoptotic signaling through the RPA/ATRIP/ATR/Chk1/p53/Puma axis, ultimately leading to the apoptotic demise of ATM-defective cells exposed to DNA-PKcs inhibitors. Finally, we demonstrate that DNA-PKcs inhibitors are effective as single agents against ATM-defective lymphomas in vivo. Together, our data implicate DNA-PKcs as a drug target for the treatment of ATM-defective malignancies.
authors.affiliation: Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany.
authors.forename: Arina
authors.initials: A
authors.lastname: Riabinska
authors.forename: Mathias
authors.initials: M
authors.lastname: Daheim
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.forename: Johannes
authors.initials: J
authors.lastname: Winkler
authors.forename: Christian
authors.initials: C
authors.lastname: Fritz
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.forename: Parisa
authors.initials: P
authors.lastname: Monfared
authors.forename: Jorge
authors.initials: J
authors.lastname: Martins-Boucas
authors.forename: Shuhua
authors.initials: S
authors.lastname: Chen
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse