Next Article in Journal
In Vivo Evaluation of Dual-Targeted Nanoparticles Encapsulating Paclitaxel and Everolimus
Next Article in Special Issue
Aberrant MicroRNA Expression and Its Implications for Uveal Melanoma Metastasis
Previous Article in Journal
Molecular Characterization of a Long-Term Survivor Double Metastatic Non-Small Cell Lung Cancer and Pancreatic Ductal Adenocarcinoma Treated with Gefitinib in Combination with Gemcitabine Plus Nab-Paclitaxel and mFOLFOX6 as First and Second Line Therapy
Previous Article in Special Issue
Changes in Ultraviolet Radiation Exposure to the Ocular Region: A Population-Based Study
Article Menu
Issue 6 (June) cover image

Export Article

Open AccessArticle

PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

1
RPPA Platform, Department of Translational Research, Institut Curie, PSL University, 75248 Paris, France
2
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, 75248 Paris, France
3
Department of Medical Oncology, Institut Curie, 75248 Paris, France
4
Department of Tumor Biology, Institut Curie, 75248 Paris, France
5
Novartis Institutes for BioMedical Research, Translational Clinical Oncology, Cambridge, MA 02139, USA
6
Oncology IMED, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK
7
Genomics Platform, Department of Translational Research, Institut Curie, PSL University, 75248 Paris, France
8
Department of Surgery, Institut Curie, 75248 Paris, France
9
Department of Ophthalmologic Surgery, Institut Curie, University of Medicine René Descartes Paris V, 75248 Paris, France
10
Department of Translational Research, Institut Curie, PSL University, 75248 Paris, France
*
Authors to whom correspondence should be addressed.
These two authors have contributed equally to this work.
Cancers 2019, 11(6), 751; https://doi.org/10.3390/cancers11060751
Received: 13 March 2019 / Revised: 16 May 2019 / Accepted: 27 May 2019 / Published: 29 May 2019
(This article belongs to the Special Issue Uveal Melanoma)
  |  
PDF [5033 KB, uploaded 21 June 2019]
  |     |  

Abstract

Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations. However, no data on DNA repair capacities in UM are available. Here, we use UM patient-derived xenografts (PDXs) to study the therapeutic activity of the PARP inhibitor olaparib, alone or in combination. First, we show that the expression and the activity of PARP proteins is similar between the PDXs and the corresponding patient’s tumors. In vivo experiments in the PDX models showed that olaparib was not efficient alone, but significantly increased the efficacy of dacarbazine. Finally, using reverse phase protein arrays and immunohistochemistry, we identified proteins involved in DNA repair and apoptosis as potential biomarkers predicting response to the combination of olaparib and dacarbazine. We also observed a high increase of phosphorylated YAP and TAZ proteins after dacarbazine + olaparib treatment. Our results suggest that PARP inhibition in combination with the alkylating agent dacarbazine could be of clinical interest for UM treatment. We also observe an interesting effect of dacarbazine on the Hippo pathway, confirming the importance of this pathway in UM. View Full-Text
Keywords: PARP inhibitor; treatment combinations; uveal melanomas; patient-derived xenografts PARP inhibitor; treatment combinations; uveal melanomas; patient-derived xenografts
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

de Koning, L.; Decaudin, D.; El Botty, R.; Nicolas, A.; Carita, G.; Schuller, M.; Ouine, B.; Cartier, A.; Naguez, A.; Fleury, J.; Cooke, V.; Wylie, A.; Smith, P.; Marangoni, E.; Gentien, D.; Meseure, D.; Mariani, P.; Cassoux, N.; Piperno-Neumann, S.; Roman-Roman, S.; Némati, F. PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma. Cancers 2019, 11, 751.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top