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Eur J Cancer. 2014 Oct;50(15):2725-34. doi: 10.1016/j.ejca.2014.07.004. Epub 2014 Aug 12.

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

Author information

1
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
2
Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
3
Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain.
4
Institute of Health Research INCLIVA, Valencia, Spain.
5
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain; Autonomous University of Barcelona, Spain.
6
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Immunology Department, Hospital del Mar, Barcelona, Spain.
7
Oncology and Hematology Department, Hospital Clinico Universitario, Valencia, Spain; Valencia Central University, Spain.
8
Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain; Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain.
9
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain; Pathology Department, Hospital del Mar, Barcelona, Spain.
10
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: jalbanell@hospitaldelmar.cat.

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.

KEYWORDS:

Breast cancer; HER2; Olaparib; PARP; Rucaparib; Trastuzumab

PMID:
25128455
DOI:
10.1016/j.ejca.2014.07.004
[Indexed for MEDLINE]

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