PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma
AbstractUveal 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
- Supplementary File 1:
PDF-Document (PDF, 6360 KB)
Share & Cite This Article
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.
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(6):751.Chicago/Turabian Style
de Koning, Leanne; Decaudin, Didier; El Botty, Rania; Nicolas, André; Carita, Guillaume; Schuller, Mathieu; Ouine, Bérengère; Cartier, Aurélie; Naguez, Adnan; Fleury, Justine; Cooke, Vesselina; Wylie, Andrew; Smith, Paul; Marangoni, Elisabetta; Gentien, David; Meseure, Didier; Mariani, Pascale; Cassoux, Nathalie; Piperno-Neumann, Sophie; Roman-Roman, Sergio; Némati, Fariba. 2019. "PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma." Cancers 11, no. 6: 751.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.