title: Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53.
abstract: Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies.
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: Eiji
authors.initials: E
authors.lastname: Kubota
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hamill
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimowicz
authors.forename: Ruiqiong
authors.initials: R
authors.lastname: Ye
authors.forename: Huong
authors.initials: H
authors.lastname: Muzik
authors.forename: Michelle
authors.initials: M
authors.lastname: Dean
authors.forename: LiRen
authors.initials: L
authors.lastname: Tu
authors.forename: David
authors.initials: D
authors.lastname: Gilley
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
authors.forename: Bruce C
authors.initials: BC
authors.lastname: McKay
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; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000473:pathology; D051379:Mice; D009154:Mutation; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C531550:olaparib