title: ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Williamson
authors.forename: Huong
authors.initials: H
authors.lastname: Muzik
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
authors.forename: Alberto
authors.initials: A
authors.lastname: Zamò
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: D Gwyn
authors.initials: DG
authors.lastname: Bebb
authors.forename: Susan P
authors.initials: SP
authors.lastname: Lees-Miller
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011839:Radiation, Ionizing; D014343:Trypan Blue / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D014343:Trypan Blue; C531550:olaparib