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

Author:

Weston Victoria J.1,Oldreive Ceri E.1,Skowronska Anna1,Oscier David G.2,Pratt Guy3,Dyer Martin J. S.4,Smith Graeme5,Powell Judy E.6,Rudzki Zbigniew7,Kearns Pamela1,Moss Paul A. H.1,Taylor A. Malcolm R.1,Stankovic Tatjana1

Affiliation:

1. School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;

2. Haematology Department, Royal Bournemouth Hospital, Dorset, United Kingdom;

3. Haematology Department, Heartlands Hospital, Birmingham, United Kingdom;

4. Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, United Kingdom;

5. AstraZeneca Pharmaceuticals, Cambridge, United Kingdom;

6. School of Health and Population Sciences, University of Birmingham, Birmingham, United Kingdom; and

7. Pathology Department, Heartlands Hospital, Birmingham, United Kingdom

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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