Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells
In head and neck squamous cell carcinoma (HNSCC), tumors positive for human papillomavirus (HPV) represent a distinct biological entity with favorable prognosis. An enhanced radiation sensitivity of these tumors is evident in the clinic and on the cellular level when comparing HPV-positive and HPV-n...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.683688/full |
| _version_ | 1819144017493884928 |
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| author | Katharina Hintelmann Katharina Hintelmann Thomas Berenz Thomas Berenz Malte Kriegs Sabrina Christiansen Sabrina Christiansen Fruzsina Gatzemeier Fruzsina Gatzemeier Nina Struve Nina Struve Cordula Petersen Christian Betz Kai Rothkamm Agnes Oetting Agnes Oetting Thorsten Rieckmann Thorsten Rieckmann |
| author_facet | Katharina Hintelmann Katharina Hintelmann Thomas Berenz Thomas Berenz Malte Kriegs Sabrina Christiansen Sabrina Christiansen Fruzsina Gatzemeier Fruzsina Gatzemeier Nina Struve Nina Struve Cordula Petersen Christian Betz Kai Rothkamm Agnes Oetting Agnes Oetting Thorsten Rieckmann Thorsten Rieckmann |
| author_sort | Katharina Hintelmann |
| collection | DOAJ |
| description | In head and neck squamous cell carcinoma (HNSCC), tumors positive for human papillomavirus (HPV) represent a distinct biological entity with favorable prognosis. An enhanced radiation sensitivity of these tumors is evident in the clinic and on the cellular level when comparing HPV-positive and HPV-negative HNSCC cell lines. We could show that the underlying mechanism is a defect in DNA double-strand break repair associated with a profound and sustained G2 arrest. This defect can be exploited by molecular targeting approaches additionally compromising the DNA damage response to further enhance their radiation sensitivity, which may offer new opportunities in the setting of future de-intensified regimes. Against this background, we tested combined targeting of PARP and the DNA damage-induced intra-S/G2 cell cycle checkpoints to achieve effective radiosensitization. Enhancing CDK1/2 activity through the Wee1 inhibitor adavosertib or a combination of Wee1 and Chk1 inhibition resulted in an abrogation of the radiation-induced G2 cell cycle arrest and induction of replication stress as assessed by γH2AX and chromatin-bound RPA levels in S phase cells. Addition of the PARP inhibitor olaparib had little influence on these endpoints, irrespective of checkpoint inhibition. Combined PARP/Wee1 targeting did not result in an enhancement in the absolute number of residual, radiation induced 53BP1 foci as markers of DNA double-strand breaks but it induced a shift in foci numbers from S/G2 to G1 phase cells. Most importantly, while sole checkpoint or PARP inhibition induced moderate radiosensitization, their combination was clearly more effective, while exerting little effect in p53/G1 arrest proficient normal human fibroblasts, thus indicating tumor specificity. We conclude that the combined inhibition of PARP and the intra-S/G2 checkpoint is a highly effective approach for the radiosensitization of HPV-positive HNSCC cells and may represent a viable alternative for the current standard of concomitant cisplatin-based chemotherapy. In vivo studies to further evaluate the translational potential are highly warranted. |
| first_indexed | 2024-12-22T12:35:27Z |
| format | Article |
| id | doaj.art-71bf6c2be32f4eddaabc06b915945429 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T12:35:27Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-71bf6c2be32f4eddaabc06b9159454292022-12-21T18:25:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-07-011110.3389/fonc.2021.683688683688Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC CellsKatharina Hintelmann0Katharina Hintelmann1Thomas Berenz2Thomas Berenz3Malte Kriegs4Sabrina Christiansen5Sabrina Christiansen6Fruzsina Gatzemeier7Fruzsina Gatzemeier8Nina Struve9Nina Struve10Cordula Petersen11Christian Betz12Kai Rothkamm13Agnes Oetting14Agnes Oetting15Thorsten Rieckmann16Thorsten Rieckmann17Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyMildred-Scheel Cancer Career Center HATRICs4, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Radiotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyIn head and neck squamous cell carcinoma (HNSCC), tumors positive for human papillomavirus (HPV) represent a distinct biological entity with favorable prognosis. An enhanced radiation sensitivity of these tumors is evident in the clinic and on the cellular level when comparing HPV-positive and HPV-negative HNSCC cell lines. We could show that the underlying mechanism is a defect in DNA double-strand break repair associated with a profound and sustained G2 arrest. This defect can be exploited by molecular targeting approaches additionally compromising the DNA damage response to further enhance their radiation sensitivity, which may offer new opportunities in the setting of future de-intensified regimes. Against this background, we tested combined targeting of PARP and the DNA damage-induced intra-S/G2 cell cycle checkpoints to achieve effective radiosensitization. Enhancing CDK1/2 activity through the Wee1 inhibitor adavosertib or a combination of Wee1 and Chk1 inhibition resulted in an abrogation of the radiation-induced G2 cell cycle arrest and induction of replication stress as assessed by γH2AX and chromatin-bound RPA levels in S phase cells. Addition of the PARP inhibitor olaparib had little influence on these endpoints, irrespective of checkpoint inhibition. Combined PARP/Wee1 targeting did not result in an enhancement in the absolute number of residual, radiation induced 53BP1 foci as markers of DNA double-strand breaks but it induced a shift in foci numbers from S/G2 to G1 phase cells. Most importantly, while sole checkpoint or PARP inhibition induced moderate radiosensitization, their combination was clearly more effective, while exerting little effect in p53/G1 arrest proficient normal human fibroblasts, thus indicating tumor specificity. We conclude that the combined inhibition of PARP and the intra-S/G2 checkpoint is a highly effective approach for the radiosensitization of HPV-positive HNSCC cells and may represent a viable alternative for the current standard of concomitant cisplatin-based chemotherapy. In vivo studies to further evaluate the translational potential are highly warranted.https://www.frontiersin.org/articles/10.3389/fonc.2021.683688/fullhead and neck cancerhuman papillomavirus (HPV)molecular targetingradiotherapyradiosensitizationPARP |
| spellingShingle | Katharina Hintelmann Katharina Hintelmann Thomas Berenz Thomas Berenz Malte Kriegs Sabrina Christiansen Sabrina Christiansen Fruzsina Gatzemeier Fruzsina Gatzemeier Nina Struve Nina Struve Cordula Petersen Christian Betz Kai Rothkamm Agnes Oetting Agnes Oetting Thorsten Rieckmann Thorsten Rieckmann Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells Frontiers in Oncology head and neck cancer human papillomavirus (HPV) molecular targeting radiotherapy radiosensitization PARP |
| title | Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells |
| title_full | Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells |
| title_fullStr | Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells |
| title_full_unstemmed | Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells |
| title_short | Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells |
| title_sort | dual inhibition of parp and the intra s g2 cell cycle checkpoints results in highly effective radiosensitization of hpv positive hnscc cells |
| topic | head and neck cancer human papillomavirus (HPV) molecular targeting radiotherapy radiosensitization PARP |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.683688/full |
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