Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer

Jetzabel García-Parra, Alba Dalmases, Beatriz Morancho, Oriol Arpí, Silvia Menendez, Mohammada Sabbaghi, Sandra Zazo, Cristina Chamizo, Juan Madoz, Pilar Eroles, Sonia Servitja, Ignasi Tusquets, Jose Yelamos, Ana Lluch, Joaquin Arribas, Federico Rojo, Ana Rovira, Joan Albanell

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

© 2014 Elsevier Ltd. All rights reserved. Aim Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies.Methods We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells.Results In a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis.Conclusion Taken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development. © 2014 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)2725-2734
JournalEuropean Journal of Cancer
Volume50
Issue number15
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Breast cancer
  • HER2
  • Olaparib
  • PARP
  • Rucaparib
  • Trastuzumab

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