Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Victoria J. Weston1,*,
  2. Ceri E. Oldreive1,*,
  3. Anna Skowronska1,
  4. David G. Oscier2,
  5. Guy Pratt3,
  6. Martin J. S. Dyer4,
  7. Graeme Smith5,
  8. Judy E. Powell6,
  9. Zbigniew Rudzki7,
  10. Pamela Kearns1,
  11. Paul A. H. Moss1,
  12. A. Malcolm R. Taylor1, and
  13. Tatjana Stankovic1
  1. 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
  2. 2Haematology Department, Royal Bournemouth Hospital, Dorset, United Kingdom;
  3. 3Haematology Department, Heartlands Hospital, Birmingham, United Kingdom;
  4. 4Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, United Kingdom;
  5. 5AstraZeneca Pharmaceuticals, Cambridge, United Kingdom;
  6. 6School of Health and Population Sciences, University of Birmingham, Birmingham, United Kingdom; and
  7. 7Pathology Department, Heartlands Hospital, Birmingham, United Kingdom

Abstract

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (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 repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase 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. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

  • Submitted January 20, 2010.
  • Accepted August 2, 2010.
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