PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma.

Leanne De Koning,Didier Meseure,Nathalie Cassoux,Elisabetta Marangoni,Mathieu Schuller,Guillaume Carita,Adnan Naguez,Didier Decaudin,David Gentien,Andrew Wylie,Rania El Botty,Justine Fleury,Pascale Mariani,André Nicolas,Aurélie Cartier,Fariba Némati,Paul D Smith ,Sergio Román-Román ,Bérengère Ouine ,Sophie Piperno‐Neumann ,Vesselina G Cooke

doi:10.3390/cancers11060751

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.

Highlights

Uveal melanoma (UM) is a rare tumor affecting 7/1.0 million of the Western population per year [1] for which no effective systemic therapies exist at the metastatic stage
Using Reverse Phase Protein Array Study (RPPA), Western Blot (WB), and IHC analyses, we explored predictive factors that are implicated in the additive effect of olaparib + dacarbazine, as well as protein modifications observed in treated tumors
We aimed to evaluate the therapeutic potential of the PARP inhibitor olaparib in UM patient-derived xenografts (PDXs) for the first time

Summary

Introduction

Uveal melanoma (UM) is a rare tumor affecting 7/1.0 million of the Western population per year [1] for which no effective systemic therapies exist at the metastatic stage. Dacarbazine (DTIC), which is an alkylating agent leading to DNA lesions, is often the standard arm in trials in metastatic. The MEK1/2 inhibitor selumetinib, in combination with dacarbazine, fails to improve progression-free survival of metastatic UM [10]. Various targeted therapies have been tested in combination with selumetinib [11] or with the PKC (protein kinase C) inhibitor AEB071 [12] in UM preclinical models, and in patient-derived xenografts (PDXs). On this basis, this last compound is currently being tested in a clinical trial, currently in combination with a MDM2 inhibitor (NCT02601378)

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