Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts

Ádám Póti, Kinga Berta, Yonghong Xiao, Orsolya Pipek, Gregory T. Klus, Thomas Ried, István Csabai, Keith Wilcoxen, Keith Mikule, Zoltan Szallasi, Dávid Szüts

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1392-1400
Number of pages9
JournalBritish journal of cancer
Volume119
Issue number11
DOIs
Publication statusPublished - Nov 27 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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