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Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

ABSTRACT: Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

SUBMITTER: Bonadio RC

PROVIDER: S-EPMC8715945 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

Bonadio Renata Colombo RC Estevez-Diz Maria Del Pilar MDP

Frontiers in oncology 20211215

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent i ...[more]

PMID: 34976801

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Project description:BackgroundBreast and ovarian cancers are common malignancies among women, contributing to a significant disease burden, and are characterized by a high level of genomic instability, owing to the failure of homologous recombination repair (HRR). Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) could elicit the synthetic lethal effect of tumor cells in patients with homologous recombination deficiency, ultimately achieving a favorable clinical benefit. However, primary and acquired resistance remain the greatest hurdle, limiting the efficacy of PARP inhibitors; thus, strategies conferring or augmenting tumor cell sensitivity to PARP inhibitors are urgently required.MethodsOur RNA-seq data of niraparib-treated and -untreated tumor cells were analyzed by R language. Gene Set Enrichment Analysis (GSEA) was applied to assess the biological functions of GTP cyclohydrolase 1 (GCH1). Quantitative real-time PCR, Western blotting, and immunofluorescence were applied to confirm the upregulation of GCH1 upon niraparib treatment at transcriptional and translational levels. Immunohistochemistry of patient-derived xenograft (PDX)-derived tissue sections further validated that niraparib increased GCH1 expression. Tumor cell apoptosis was detected by flow cytometry, while the superiority of the combination strategy was confirmed in the PDX model.ResultsThe expression of GCH1 was aberrantly enriched in breast and ovarian cancers and increased after niraparib treatment via JAK-STAT signaling. GCH1 was also demonstrated to be associated with the HRR pathway. Subsequently, the enhancement of the tumor-killing effect of PARP inhibitors induced by GCH1 suppression using siRNA and GCH1 inhibitor was validated by flow cytometry in vitro. Finally, using the PDX model, we further demonstrated that GCH1 inhibitors markedly potentiated PARP inhibitors' antitumor efficacy in vivo.ConclusionOur results illustrated that PARP inhibitors promote GCH1 expression via the JAK-STAT pathway. We also elucidated the potential relationship between GCH1 and the homologous recombination repair pathway and proposed a combination regimen of GCH1 suppression with PARP inhibitors in breast and ovarian cancers.

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Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

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Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

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