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

Abstract

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.

• Authors: 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
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 50 Issue 15 Pg. 2725-34 (Oct 2014) ISSN: 1879-0852 [Electronic] England
• PMID: 25128455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• H2AX protein, human
• Histones
• Indoles
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Proliferating Cell Nuclear Antigen
• rucaparib
• Poly(ADP-ribose) Polymerases
• Receptor, ErbB-2
• Trastuzumab
• olaparib

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Damage
• Female
• Histones (metabolism)
• Humans
• Indoles (administration & dosage, pharmacology)
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Nude
• Phthalazines (administration & dosage, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Proliferating Cell Nuclear Antigen (genetics, metabolism)
• RNA Interference
• Receptor, ErbB-2 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Trastuzumab
• Treatment Outcome
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays