Cited by 194PARP inhibition in cancer therapyDNA Repair MechanismsChronic Lymphocytic Leukemia Research

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ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors

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Williamson, Chris T., Muzik, Huong, Turhan, Ali G., Zamò, Alberto, O'Connor, Mark J., Bebb, D. Gwyn, Lees-Miller, Susan P.·2010·Molecular Cancer Therapeutics

DOI 10.1158/1535-7163.mct-09-0872PMC PMC3729269

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Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations. Mol Cancer Ther; 9(2); 347–57

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Authors: Williamson, C. T., Muzik, H., Turhan, A. G., Zamò, A., O'Connor, M. J., Bebb, D. G., & Lees-Miller, S. P.
Affiliations: University of Verona (IT)
Authors' Affiliations: Departments of 1Biochemistry and Molecular Biology and 2Oncology and 3Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada; 4Inserm U935, University of Poitiers and Service d'Hématologie et d'Oncologie Biologique EA 3805, CHU de Poitiers, Poitiers, France; 5Dipartimento di Patologia, Sezione di Anatomia Patologica, University of Verona, Verona, Italy; and 6KuDOS Pharmaceuticals, Cambridge, United Kingdom
Corresponding author: Bebb, D. Gwyn
ORCID: Turhan, Ali G.
Zamò, Alberto
Bebb, D. Gwyn
Venue: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research (AACR)
Published: 2010-02-01
Volume: 9
Issue: 2
Pages: 347-357
ISSN: 1535-7163 (ISSN-L)
1538-8514
DOI: 10.1158/1535-7163.mct-09-0872
PMC: PMC3729269
OpenAlex: W2103272465
Cited by: 193
References: 54
Citations by year: 2026: 2 · 2025: 6 · 2024: 4 · 2023: 16 · 2022: 4 · 2021: 6 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 12 · 2016: 13 · 2015: 17 · 2014: 12 · 2013: 20 · 2012: 20
FWCI: 9.95
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Molecular Cancer Therapeutics (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders: Canadian Institutes of Health Research
National Cancer Institute (P01-CA 92584, P01CA092584)
Topics: Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Keywords: mantle cell lymphoma, ATM deficiency, PARP-1 inhibitors, olaparib, synthetic lethality, DNA repair deficiency, radiosensitivity, xenograft tumor growth, overall survival
MeSH terms: Poly(ADP-ribose) Polymerase Inhibitors, Animals, DNA Repair, DNA-Binding Proteins, Female, Humans, Neoplasm Transplantation, Phosphorylation, Phthalazines, Piperazines, Radiation, Ionizing, Trypan Blue, Annexin A5, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Lymphoma, Mantle-Cell, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Ataxia Telangiectasia Mutated Proteins

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ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors

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