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PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

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

in Apoptosis / BRCA1 protein / Cancer therapies / Cell cycle / Chemotherapy / Clinical trials / Dacarbazine / Deoxyribonucleic acid / DNA / DNA damage / DNA repair / Gene expression / Genomics / Immunohistochemistry / Kinases / Melanoma / Metastases / Metastasis / Mutation / n/a / Oncology / Patients / Poly(ADP-ribose) polymerase / Protein arrays / Protein expression / Proteins / Tumors / Xenografts / Yes-associated protein

2019

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PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

2019

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PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

2019

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Journal Article

PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

Paul Smith,

Mathieu Schuller,

David Gentien,

Leanne de Koning,

Pascale Mariani,

Vesselina Cooke,

André Nicolas,

Adnan Naguez,

Rania El Botty,

Justine Fleury,

Andrew Wylie,

Elisabetta Marangoni,

Nathalie Cassoux,

Aurélie Cartier,

Fariba Némati,

Didier Decaudin,

Didier Meseure,

Bérengère Ouine,

Guillaume Carita,

Sophie Piperno-Neumann,

Sergio Roman-Roman

2019

Overview

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.

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MDPI AG,MDPI

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