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

  title={The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.},
  author={Victoria J. Weston and Ceri E Oldreive and Anna Skowrońska and David Oscier and Guy Pratt and Martin J. S. Dyer and Graeme C.M. Smith and Judith E. Powell and Zbigniew Rudzki and Pamela R. Kearns and Paul Moss and A. Malcolm R. Taylor and Tatjana Stankovic},
  volume={116 22},
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… 

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Olaparib Induced Moderate Killing of ATM -Deficient Mantle Cell Lymphoma Cells In Vitro and In Vivo

In vitro and in vivo sensitivity to the PARP inhibitor olaparib in the ATM deficient mantle cell lymphoma cell line Granta-519 is investigated and decreased proliferation in vitro and vivo is confirmed.

Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53

It is shown 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, and the combination of ATM and PARP inhibitors may have utility in targeting p53‐deficient malignancies.

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

It is shown that olaparib combines synergistically with the ATR-inhibitor AZD6738, in vitro, leading to selective cell death in ATM-deficient cells, suggesting that combined treatment could circumvent the need for prolonged drug exposure.

Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines

It is reported that PARP inhibitors can potentially target ATM deficiency arising in a solid malignancy and combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARp-1 inhibitors to gastric cancer with p53 disruption.

ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe.

ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition

It is indicated that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.

Targeting ATM-deficient CLL through interference with DNA repair pathways

The role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis is focused on and the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones are highlighted.

PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia

PARP activity is highly variable in CLL and correlates with stress-induced proteins, and Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.



Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage.

It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregersminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.

Nuclear Ataxia-Telangiectasia Mutated (ATM) Mediates the Cellular Response to DNA Double Strand Breaks in Human Neuron-like Cells*

It is concluded that nuclear ATM mediates the DSB response in NLCs similarly to in proliferating cells, and attempts to understand the neurodegeneration in A-T should be directed to investigating the D SB response in the nervous system.

A Double-Strand Break Repair Defect in ATM-Deficient Cells Contributes to Radiosensitivity

It is argued that the DSB repair defect underlies a significant component of the radiosensitivity of AT cells, which is more pronounced than that of NHEJ mutants and correlates with radiosensitivity after biologically relevant radiation doses and long repair times.

Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM

KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase, which did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage.

Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair

It is suggested that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs) in non-homologous end joining (NHEJ).

Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses.

Damage-induced transcriptional fingerprinting can be used to stratify tumors according to their biologic differences and simultaneously identify potential targets for treating refractory tumors.

p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation.

It is shown that p53 dysfunction in B-cell chronic lymphocytic leukemia (CLL) can occur in the absence of TP53 mutation and that such dysfunction is associated with mutation of the gene encoding ATM, a kinase implicated in p53 activation.

Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion.

It is demonstrated that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion and that patients with complete loss of ATM function have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome.

Mantle cell lymphoma is characterized by inactivation of the ATM gene.

The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicates that ATM plays a role in the initiation and/or progression of MCL.

The controlling role of ATM in homologous recombinational repair of DNA damage

Results reveal that ATM defects impair HR‐mediated dsb repair and may link cell cycle checkpoints to HR activation, placing ATM and HR on the same pathway.