Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours
Abstract The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication‐associated DNA damage and genomic instability, a signature of BRCA1/2‐mutated tumours. Targeted therapies against BRCA1/2‐mutated tumours exploit this vulnerability...
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Springer Nature
2022-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114501 |
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| author | Florian J Groelly Manuela Porru Jutta Zimmer Hugo Benainous Yanti De Visser Anastasiya A Kosova Serena Di Vito Violeta Serra Anderson Ryan Carlo Leonetti Alejandra Bruna Annamaria Biroccio Madalena Tarsounas |
| author_facet | Florian J Groelly Manuela Porru Jutta Zimmer Hugo Benainous Yanti De Visser Anastasiya A Kosova Serena Di Vito Violeta Serra Anderson Ryan Carlo Leonetti Alejandra Bruna Annamaria Biroccio Madalena Tarsounas |
| author_sort | Florian J Groelly |
| collection | DOAJ |
| description | Abstract The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication‐associated DNA damage and genomic instability, a signature of BRCA1/2‐mutated tumours. Targeted therapies against BRCA1/2‐mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue. Ligands that bind and stabilise G‐quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate the cells and tumours lacking BRCA1 or BRCA2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2‐deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here, we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2‐deficient tumours, including patient‐derived xenograft tumours that have acquired PARP inhibitor (PARPi) resistance. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double‐stranded breaks (DSBs) that can be repaired in the absence of BRCA1/2 by canonical non‐homologous end joining (C‐NHEJ). Consistent with this, chemical inhibitors of DNA‐PKcs, a core component of C‐NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2‐deficient cells and tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING‐dependent innate immune responses when BRCA1 or BRCA2 is abrogated. Paclitaxel, a drug routinely used in cancer chemotherapy, potentiates the in vivo toxicity of pyridostatin. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA‐PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations. |
| format | Article |
| id | doaj-art-02c619b0acf544c3b51f32c37322ca42 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-02c619b0acf544c3b51f32c37322ca422025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-02-0114312210.15252/emmm.202114501Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumoursFlorian J Groelly0Manuela Porru1Jutta Zimmer2Hugo Benainous3Yanti De Visser4Anastasiya A Kosova5Serena Di Vito6Violeta Serra7Anderson Ryan8Carlo Leonetti9Alejandra Bruna10Annamaria Biroccio11Madalena Tarsounas12Genome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordArea of Translational Research, IRCCS Regina Elena National Cancer InstituteGenome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordGenome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordGenome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordGenome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordArea of Translational Research, IRCCS Regina Elena National Cancer InstituteExperimental Therapeutics Group, Vall d’Hebron Institute of OncologyLung Cancer Translational Science Research Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordArea of Translational Research, IRCCS Regina Elena National Cancer InstituteMolecular Pathology Division, Centre for Cancer Evolution, The Institute of Cancer ResearchArea of Translational Research, IRCCS Regina Elena National Cancer InstituteGenome Stability and Tumourigenesis Group, The MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordAbstract The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication‐associated DNA damage and genomic instability, a signature of BRCA1/2‐mutated tumours. Targeted therapies against BRCA1/2‐mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue. Ligands that bind and stabilise G‐quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate the cells and tumours lacking BRCA1 or BRCA2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2‐deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here, we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2‐deficient tumours, including patient‐derived xenograft tumours that have acquired PARP inhibitor (PARPi) resistance. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double‐stranded breaks (DSBs) that can be repaired in the absence of BRCA1/2 by canonical non‐homologous end joining (C‐NHEJ). Consistent with this, chemical inhibitors of DNA‐PKcs, a core component of C‐NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2‐deficient cells and tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING‐dependent innate immune responses when BRCA1 or BRCA2 is abrogated. Paclitaxel, a drug routinely used in cancer chemotherapy, potentiates the in vivo toxicity of pyridostatin. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA‐PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations.https://doi.org/10.15252/emmm.202114501BRCA1BRCA2DNA damage responsesG‐quadruplex ligandspyridostatin |
| spellingShingle | Florian J Groelly Manuela Porru Jutta Zimmer Hugo Benainous Yanti De Visser Anastasiya A Kosova Serena Di Vito Violeta Serra Anderson Ryan Carlo Leonetti Alejandra Bruna Annamaria Biroccio Madalena Tarsounas Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours EMBO Molecular Medicine BRCA1 BRCA2 DNA damage responses G‐quadruplex ligands pyridostatin |
| title | Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours |
| title_full | Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours |
| title_fullStr | Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours |
| title_full_unstemmed | Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours |
| title_short | Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours |
| title_sort | anti tumoural activity of the g quadruplex ligand pyridostatin against brca1 2 deficient tumours |
| topic | BRCA1 BRCA2 DNA damage responses G‐quadruplex ligands pyridostatin |
| url | https://doi.org/10.15252/emmm.202114501 |
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