PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

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.

Tanshinone I and simvastatin inhibit melanoma tumour cell growth by regulating poly (ADP ribose) polymerase 1 expression

“…Detection of PARP1 expression in this study indicated that, besides the enzymatic activity of PARP1, PARP1 expression may be important for carcinogenesis. Olaparib increased the response to dacarbazine, an alkylating agent, in a patient-derived xenograft model of uveal melanoma (8). Although veliparib and olaparib have been reported to increase the sensitivity of various histological subtypes of SNP carrier cancer cells to alkylating agents, they have no effect on wild-type cells (11).…”

“…BRAF), and there is no effective therapy for melanoma at the metastatic stage (e.g. uveal melanoma) (8). Veliparib has been reported to be effective in the treatment of BRAF inhibitor-resistant Tanshinone I and simvastatin inhibit melanoma tumour cell growth by regulating poly (ADP ribose) polymerase 1 expression melanoma cells (9).…”

“…However, while a randomized phase II study of veliparib with temozolomide demonstrated a higher median progression-free survival for veliparib compared with that of the placebo, the difference was not statistically significant (10). Besides, while olaparib increased response to dacarbazine (an alkylating agent) in uveal melanoma (8), both veliparib and olaparib combined increased the sensitivity of various histological subtypes of single-nucleotide polymorphism (SNP)-carrier cancer cells to alkylating agents, without an effect on wild-type cells (11).…”

Current Molecular Markers of Melanoma and Treatment Targets

“…Therapeutic targeting of BAP1 has focused on its role in DNA double-strand break repair via homologous recombination [130]. Mutations in BAP1 thus have been hypothesized to rely on alternative mechanisms of DNA repair with poly (ADP-ribose) polymerase (PARP) emerging as a target for its role in base-excision and nucleotide excision repair [131]. A phase II trial is recruiting to evaluate the effect of niraparib, a PARP inhibitor, in the treatment of uveal melanoma (NCT03207347) [74].…”

Uveal Melanoma

“…Tura et al provide data indicating that the therapeutic antibody ranibizumab, and not bevacizumab, suppresses metabolic activity, proliferation, and intracellular Vascular Endothelial Growth Factor A, VEGF-A, levels in uveal melanoma [38]. De Koning et al report on synergistic effects of poly-ADP ribose polymerase inhibitors and chemotherapy that might rely on inhibition of YAP/TAZ signaling [42].…”