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Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1

Standard

Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1. / Oetting, Agnes; Christiansen, Sabrina; Gatzemeier, Fruzsina; Köcher, Sabrina; Bußmann, Lara; Böttcher, Arne; Stölzel, Katharina; Hoffmann, Anna Sophie; Struve, Nina; Kriegs, Malte; Petersen, Cordula; Betz, Christian; Rothkamm, Kai; Zech, Henrike Barbara; Rieckmann, Thorsten.

in: CLIN TRANSL RAD ONCO, Jahrgang 41, 07.2023, S. 100630.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Oetting, A, Christiansen, S, Gatzemeier, F, Köcher, S, Bußmann, L, Böttcher, A, Stölzel, K, Hoffmann, AS, Struve, N, Kriegs, M, Petersen, C, Betz, C, Rothkamm, K, Zech, HB & Rieckmann, T 2023, 'Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1', CLIN TRANSL RAD ONCO, Jg. 41, S. 100630. https://doi.org/10.1016/j.ctro.2023.100630

APA

Oetting, A., Christiansen, S., Gatzemeier, F., Köcher, S., Bußmann, L., Böttcher, A., Stölzel, K., Hoffmann, A. S., Struve, N., Kriegs, M., Petersen, C., Betz, C., Rothkamm, K., Zech, H. B., & Rieckmann, T. (2023). Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1. CLIN TRANSL RAD ONCO, 41, 100630. https://doi.org/10.1016/j.ctro.2023.100630

Vancouver

Oetting A, Christiansen S, Gatzemeier F, Köcher S, Bußmann L, Böttcher A et al. Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1. CLIN TRANSL RAD ONCO. 2023 Jul;41:100630. https://doi.org/10.1016/j.ctro.2023.100630

Bibtex

@article{8cf82086ef93491d89ae0755f7df32e3,
title = "Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1",
abstract = "OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), tumors negative for Human Papillomavirus (HPV) remain a difficult to treat entity and the morbidity of current multimodal treatment is high. Radiotherapy in combination with molecular targeting could represent suitable, less toxic treatment options especially for cisplatin ineligible patients. Therefore, we tested dual targeting of PARP and the intra-S/G2 checkpoint through Wee1 inhibition for its radiosensitizing capacity in radioresistant HPV-negative HNSCC cells.MATERIALS AND METHODS: Three radioresistant HPV-negative cell lines (HSC4, SAS, UT-SCC-60a) were treated with olaparib, adavosertib and ionizing irradiation. The impact on cell cycle, G2 arrest and replication stress was assessed through flow cytometry after DAPI, phospho-histone H3 and γH2AX staining. Long term cell survival after treatment was determined through colony formation assay and DNA double-strand break (DSB) levels were assessed through quantification of nuclear 53BP1 foci in cell lines and patient-derived HPV± tumor slice cultures.RESULTS: Wee1 and dual targeting induced replication stress but failed to effectively inhibit radiation-induced G2 cell cycle arrest. Single as well as combined inhibition increased radiation sensitivity and residual DSB levels, with the largest effects induced through dual targeting. Dual targeting also enhanced residual DSB levels in patient-derived slice cultures from HPV-negative but not HPV+ HNSCC (5/7 vs. 1/6).CONCLUSION: We conclude that the combined inhibition of PARP and Wee1 results in enhanced residual DNA damage levels after irradiation and effectively sensitizes radioresistant HPV-negative HNSCC cells. Ex vivo tumor slice cultures may predict the response of individual patients with HPV-negative HNSCC to this dual targeting approach.",
author = "Agnes Oetting and Sabrina Christiansen and Fruzsina Gatzemeier and Sabrina K{\"o}cher and Lara Bu{\ss}mann and Arne B{\"o}ttcher and Katharina St{\"o}lzel and Hoffmann, {Anna Sophie} and Nina Struve and Malte Kriegs and Cordula Petersen and Christian Betz and Kai Rothkamm and Zech, {Henrike Barbara} and Thorsten Rieckmann",
note = "{\textcopyright} 2023 The Authors.",
year = "2023",
month = jul,
doi = "10.1016/j.ctro.2023.100630",
language = "English",
volume = "41",
pages = "100630",
journal = "CLIN TRANSL RAD ONCO",
issn = "2405-6308",
publisher = "Elsevier Ireland Ltd",

}

RIS

TY - JOUR

T1 - Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1

AU - Oetting, Agnes

AU - Christiansen, Sabrina

AU - Gatzemeier, Fruzsina

AU - Köcher, Sabrina

AU - Bußmann, Lara

AU - Böttcher, Arne

AU - Stölzel, Katharina

AU - Hoffmann, Anna Sophie

AU - Struve, Nina

AU - Kriegs, Malte

AU - Petersen, Cordula

AU - Betz, Christian

AU - Rothkamm, Kai

AU - Zech, Henrike Barbara

AU - Rieckmann, Thorsten

N1 - © 2023 The Authors.

PY - 2023/7

Y1 - 2023/7

N2 - OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), tumors negative for Human Papillomavirus (HPV) remain a difficult to treat entity and the morbidity of current multimodal treatment is high. Radiotherapy in combination with molecular targeting could represent suitable, less toxic treatment options especially for cisplatin ineligible patients. Therefore, we tested dual targeting of PARP and the intra-S/G2 checkpoint through Wee1 inhibition for its radiosensitizing capacity in radioresistant HPV-negative HNSCC cells.MATERIALS AND METHODS: Three radioresistant HPV-negative cell lines (HSC4, SAS, UT-SCC-60a) were treated with olaparib, adavosertib and ionizing irradiation. The impact on cell cycle, G2 arrest and replication stress was assessed through flow cytometry after DAPI, phospho-histone H3 and γH2AX staining. Long term cell survival after treatment was determined through colony formation assay and DNA double-strand break (DSB) levels were assessed through quantification of nuclear 53BP1 foci in cell lines and patient-derived HPV± tumor slice cultures.RESULTS: Wee1 and dual targeting induced replication stress but failed to effectively inhibit radiation-induced G2 cell cycle arrest. Single as well as combined inhibition increased radiation sensitivity and residual DSB levels, with the largest effects induced through dual targeting. Dual targeting also enhanced residual DSB levels in patient-derived slice cultures from HPV-negative but not HPV+ HNSCC (5/7 vs. 1/6).CONCLUSION: We conclude that the combined inhibition of PARP and Wee1 results in enhanced residual DNA damage levels after irradiation and effectively sensitizes radioresistant HPV-negative HNSCC cells. Ex vivo tumor slice cultures may predict the response of individual patients with HPV-negative HNSCC to this dual targeting approach.

AB - OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), tumors negative for Human Papillomavirus (HPV) remain a difficult to treat entity and the morbidity of current multimodal treatment is high. Radiotherapy in combination with molecular targeting could represent suitable, less toxic treatment options especially for cisplatin ineligible patients. Therefore, we tested dual targeting of PARP and the intra-S/G2 checkpoint through Wee1 inhibition for its radiosensitizing capacity in radioresistant HPV-negative HNSCC cells.MATERIALS AND METHODS: Three radioresistant HPV-negative cell lines (HSC4, SAS, UT-SCC-60a) were treated with olaparib, adavosertib and ionizing irradiation. The impact on cell cycle, G2 arrest and replication stress was assessed through flow cytometry after DAPI, phospho-histone H3 and γH2AX staining. Long term cell survival after treatment was determined through colony formation assay and DNA double-strand break (DSB) levels were assessed through quantification of nuclear 53BP1 foci in cell lines and patient-derived HPV± tumor slice cultures.RESULTS: Wee1 and dual targeting induced replication stress but failed to effectively inhibit radiation-induced G2 cell cycle arrest. Single as well as combined inhibition increased radiation sensitivity and residual DSB levels, with the largest effects induced through dual targeting. Dual targeting also enhanced residual DSB levels in patient-derived slice cultures from HPV-negative but not HPV+ HNSCC (5/7 vs. 1/6).CONCLUSION: We conclude that the combined inhibition of PARP and Wee1 results in enhanced residual DNA damage levels after irradiation and effectively sensitizes radioresistant HPV-negative HNSCC cells. Ex vivo tumor slice cultures may predict the response of individual patients with HPV-negative HNSCC to this dual targeting approach.

U2 - 10.1016/j.ctro.2023.100630

DO - 10.1016/j.ctro.2023.100630

M3 - SCORING: Journal article

C2 - 37180052

VL - 41

SP - 100630

JO - CLIN TRANSL RAD ONCO

JF - CLIN TRANSL RAD ONCO

SN - 2405-6308

ER -