The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence
Pan‐cyclin‐dependent‐kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib...
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Wiley
2025-04-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13773 |
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| author | Natalia García Flores Diego M. Fernández‐Aroca Cristina Garnés‐García Andrés Domínguez‐Calvo Jaime Jiménez‐Suárez Sebastià Sabater Pablo Fernández‐Aroca Ignacio Andrés Francisco J. Cimas Guillermo deCárcer Borja Belandia Ignacio Palmero Pablo Huertas María José Ruiz‐Hidalgo Ricardo Sánchez‐Prieto |
| author_facet | Natalia García Flores Diego M. Fernández‐Aroca Cristina Garnés‐García Andrés Domínguez‐Calvo Jaime Jiménez‐Suárez Sebastià Sabater Pablo Fernández‐Aroca Ignacio Andrés Francisco J. Cimas Guillermo deCárcer Borja Belandia Ignacio Palmero Pablo Huertas María José Ruiz‐Hidalgo Ricardo Sánchez‐Prieto |
| author_sort | Natalia García Flores |
| collection | DOAJ |
| description | Pan‐cyclin‐dependent‐kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT‐29). Dinaciclib did not alter serine‐protein kinase ATM signalling or cell cycle profiling after ionising‐radiation exposure, which have been described for other CDK inhibitors. Interestingly, in terms of apoptosis, although the combination renders a clear increase, no potentiation of the ionising‐radiation‐induced apoptosis was observed. Mechanistically, inhibition of CDK12 by dinaciclib diminishes BRCA1 expression, which decreases homologous recombination (HR) and probably promotes the nonhomologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising‐radiation‐associated cellular senescence in a TP53‐dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12–BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour. |
| format | Article |
| id | doaj-art-44ead440b44148e1b0741c44d9fcf0df |
| institution | OA Journals |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-44ead440b44148e1b0741c44d9fcf0df2025-08-20T02:16:21ZengWileyMolecular Oncology1574-78911878-02612025-04-011941265128010.1002/1878-0261.13773The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescenceNatalia García Flores0Diego M. Fernández‐Aroca1Cristina Garnés‐García2Andrés Domínguez‐Calvo3Jaime Jiménez‐Suárez4Sebastià Sabater5Pablo Fernández‐Aroca6Ignacio Andrés7Francisco J. Cimas8Guillermo deCárcer9Borja Belandia10Ignacio Palmero11Pablo Huertas12María José Ruiz‐Hidalgo13Ricardo Sánchez‐Prieto14Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainFacultad de Biología Universidad de Sevilla SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainServicio de Oncología Radioterápica Complejo Hospitalario Universitario de Albacete SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainServicio de Oncología Radioterápica Complejo Hospitalario Universitario de Albacete SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainUnidad de Biomedicina de la UCLM, Unidad asociada al CSIC Albacete SpainUnidad de Biomedicina de la UCLM, Unidad asociada al CSIC Albacete SpainLaboratorio de Senescencia Celular y Supresión Tumoral, Departamento de Biología del Cáncer Instituto de Investigaciones Biomédicas Sols‐Morreale (CSIC‐UAM) Madrid SpainFacultad de Biología Universidad de Sevilla SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainLaboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de Biomedicina Universidad de Castilla‐La Mancha Albacete SpainPan‐cyclin‐dependent‐kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT‐29). Dinaciclib did not alter serine‐protein kinase ATM signalling or cell cycle profiling after ionising‐radiation exposure, which have been described for other CDK inhibitors. Interestingly, in terms of apoptosis, although the combination renders a clear increase, no potentiation of the ionising‐radiation‐induced apoptosis was observed. Mechanistically, inhibition of CDK12 by dinaciclib diminishes BRCA1 expression, which decreases homologous recombination (HR) and probably promotes the nonhomologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising‐radiation‐associated cellular senescence in a TP53‐dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12–BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.https://doi.org/10.1002/1878-0261.13773BRCA1CDK12dinaciclibradiosensitivitysenescence |
| spellingShingle | Natalia García Flores Diego M. Fernández‐Aroca Cristina Garnés‐García Andrés Domínguez‐Calvo Jaime Jiménez‐Suárez Sebastià Sabater Pablo Fernández‐Aroca Ignacio Andrés Francisco J. Cimas Guillermo deCárcer Borja Belandia Ignacio Palmero Pablo Huertas María José Ruiz‐Hidalgo Ricardo Sánchez‐Prieto The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence Molecular Oncology BRCA1 CDK12 dinaciclib radiosensitivity senescence |
| title | The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence |
| title_full | The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence |
| title_fullStr | The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence |
| title_full_unstemmed | The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence |
| title_short | The CDK12–BRCA1 signaling axis mediates dinaciclib‐associated radiosensitivity through p53‐mediated cellular senescence |
| title_sort | cdk12 brca1 signaling axis mediates dinaciclib associated radiosensitivity through p53 mediated cellular senescence |
| topic | BRCA1 CDK12 dinaciclib radiosensitivity senescence |
| url | https://doi.org/10.1002/1878-0261.13773 |
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