The PARP inhibitor olaparib induces significant killing of ATM deficient lymphoid tumour cells in vitro and in vivo.

Research output: Contribution to journalArticlepeer-review

Abstract

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukaemia (CLL), T- prolymphocytic leukaemia (T-PLL) and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break (DSB) repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA DSB repair should selectively sensitise ATM deficient tumour cells to killing. We investigated in vitro sensitivity to the PARP inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line and 9 ATM deficient primary CLLs induced to cycle, and observed differential killing compared with ATM wildtype counterparts. Pharmacological inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A NOD/SCID murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumour load and an increased survival of animals following olaparib treatment in vivo. Addition of olaparib sensitised ATM null tumour cells to DNA damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumours.

Details

Original languageEnglish
Pages (from-to)4578-87
Number of pages10
JournalBlood
Volume116
Issue number22
Early online date25 Aug 2010
Publication statusPublished - 25 Nov 2010

Keywords

  • Animals, Antineoplastic Agents, Antineoplastic Agents: pharmacology, Antineoplastic Agents: therapeutic use, B-Cell, B-Cell: drug therapy, B-Cell: genetics, Cell Cycle Proteins, Cell Cycle Proteins: genetics, Cell Line, Cell Proliferation, Cell Proliferation: drug effects, Cells, Chronic, Cultured, DNA Damage, DNA Damage: drug effects, DNA-Binding Proteins, DNA-Binding Proteins: genetics, Gene Knockdown Techniques, Humans, Leukemia, Lymphocytic, Lymphoma, Mantle-Cell, Mantle-Cell: drug therapy, Mantle-Cell: genetics, Mice, Mutation, Phthalazines, Phthalazines: pharmacology, Phthalazines: therapeutic use, Piperazines, Piperazines: pharmacology, Piperazines: therapeutic use, Poly(ADP-ribose) Polymerases, Poly(ADP-ribose) Polymerases: antagonists & inhibi, Protein-Serine-Threonine Kinases, Protein-Serine-Threonine Kinases: genetics, SCID, Tumor, Tumor Suppressor Proteins, Tumor Suppressor Proteins: genetics