Póti, Ádám and Berta, Kinga and Xiao, Y. and Pipek, O. and Klus, G.T. and Szállási, Zoltán and Szüts, Dávid (2018) Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts. British Journal of Cancer, 119 (11). pp. 1392-1400. ISSN 0007-0920
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Abstract
Background: Poly-ADP ribose polymerase (PARP) inhibitor-based cancer therapy selectively targets cells with deficient homologous recombination repair. Considering their long-term use in maintenance treatment, any potential mutagenic effect of PARP inhibitor treatment could accelerate the development of resistance or harm non-malignant somatic cells. Methods: We tested the mutagenicity of long-term treatment with the PARP inhibitor niraparib using whole-genome sequencing of cultured cell clones and whole-exome sequencing of patient-derived breast cancer xenografts. Results: We observed no significant increase in the number and alteration in the spectrum of base substitutions, short insertions and deletions and genomic rearrangements upon niraparib treatment of human DLD-1 colon adenocarcinoma cells, wild-type and BRCA1 mutant chicken DT40 lymphoblastoma cells and BRCA1-defective SUM149PT breast carcinoma cells, except for a minor increase in specific deletion classes. We also did not detect any contribution of in vivo niraparib treatment to subclonal mutations arising in breast cancer-derived xenografts. Conclusions: The results suggest that long-term inhibition of DNA repair with PARP inhibitors has no or only limited mutagenic effect. Mutagenesis due to prolonged use of PARP inhibitors in cancer treatment is therefore not expected to contribute to the genetic evolution of resistance, generate significant immunogenic neoepitopes or induce secondary malignancies. © 2018, The Author(s).
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| Additional Information: | Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Tesaro, Waltham, MA, United States Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Export Date: 17 December 2018 CODEN: BJCAA Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesHungary; email: szuts.david@ttk.mta.hu Funding details: KTIA_NAP_13-2014-0021 Funding details: Breast Cancer Research Foundation, BCRF Funding details: NNF15OC0016584 Funding details: Magyar Tudományos Akadémia, MTA, LP2011-015 Funding details: FIEK_16-1-2016-0005 Funding text 1: We gratefully acknowledge the experimental work of Judit Baunoch at the Institute of Enzymology. This work was supported by the Hungarian Academy of Sciences (Momentum Grant LP2011-015 to D.S.); the National Research, Development and Innovation Fund of Hungary (FIEK_16-1-2016-0005 to D.S., O.P. and I.C., KTIA_NAP_13-2014-0021 to Z.S.); the Breast Cancer Research Foundation (to Z.S.); and the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.S., O.P. and I.C.). Funding text 2: Competing interests: This work was partially funded by Tesaro. Y.X., K.W. and K.M. hold Tesaro stock. The other authors declare no competing interests. Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Tesaro, Waltham, MA, United States Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Export Date: 7 January 2019 CODEN: BJCAA Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesHungary; email: szuts.david@ttk.mta.hu Funding details: KTIA_NAP_13-2014-0021 Funding details: Breast Cancer Research Foundation, BCRF Funding details: NNF15OC0016584 Funding details: Magyar Tudományos Akadémia, MTA, LP2011-015 Funding details: FIEK_16-1-2016-0005 Funding text 1: We gratefully acknowledge the experimental work of Judit Baunoch at the Institute of Enzymology. This work was supported by the Hungarian Academy of Sciences (Momentum Grant LP2011-015 to D.S.); the National Research, Development and Innovation Fund of Hungary (FIEK_16-1-2016-0005 to D.S., O.P. and I.C., KTIA_NAP_13-2014-0021 to Z.S.); the Breast Cancer Research Foundation (to Z.S.); and the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.S., O.P. and I.C.). Funding text 2: Competing interests: This work was partially funded by Tesaro. Y.X., K.W. and K.M. hold Tesaro stock. The other authors declare no competing interests. |
| Subjects: | R Medicine / orvostudomány > RB Pathology / patológia, kórtan R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 06 Mar 2019 07:14 |
| Last Modified: | 06 Mar 2019 07:14 |
| URI: | http://real.mtak.hu/id/eprint/91807 |
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