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ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors
Open accessPublished version of a preprint
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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“Finally, depletion of suv39h1 increased cell sensitivity to PARPi (Fig. 6D), consistent with previous reports that cells lacking ATM are sensitive to PARP inhibition (34,35).”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [34]
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Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198
Genome maintenance mechanisms for preventing cancer
Hoeijmakers, J. H. J. (2001) · Nature · doi:10.1038/35077232 · Cited by 3,939
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634
Self-citationDNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681
Poly(ADP-ribose): novel functions for an old molecule
Schreiber, V., Dantzer, F., Amé, J., & de MURCIA, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1963 · Cited by 1,975
DNA repair pathways as targets for cancer therapy
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Self-citationATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation
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Smith, J., Tho, L. M., Xu, N., & Gillespie, D. A. (2010) · Advances in cancer research · doi:10.1016/b978-0-12-380888-2.00003-0 · Cited by 1,331
Swisher, E. M., Lin, K. K., Oza, A. M., Scott, C. L., Giordano, H., Sun, J., Konecny, G. E., Coleman, R. L., Tinker, A. V., O'Malley, D. M., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30559-9 · Cited by 1,196
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Metadata
- 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
- Venue
- Molecular Cancer Therapeutics
- Published
- 2010-02-01
- Volume
- 9
- Issue
- 2
- Pages
- 347-357
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- 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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