Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth
Novel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets tha...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2020.01036/full |
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| author | Ling Zeng Drexell Hunter Boggs Chuan Xing Zhuo Zhang Joshua C. Anderson Narendra Wajapeyee Narendra Wajapeyee Chris Veale Markus Bredel Lewis Z. Shi James A. Bonner Christopher D. Willey Christopher D. Willey Christopher D. Willey Christopher D. Willey Eddy S. Yang Eddy S. Yang Eddy S. Yang Eddy S. Yang |
| author_facet | Ling Zeng Drexell Hunter Boggs Chuan Xing Zhuo Zhang Joshua C. Anderson Narendra Wajapeyee Narendra Wajapeyee Chris Veale Markus Bredel Lewis Z. Shi James A. Bonner Christopher D. Willey Christopher D. Willey Christopher D. Willey Christopher D. Willey Eddy S. Yang Eddy S. Yang Eddy S. Yang Eddy S. Yang |
| author_sort | Ling Zeng |
| collection | DOAJ |
| description | Novel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets that, when inhibited, exhibit potent IR sensitization are PARP1 and DNA-PKcs. However, their cooperation in sensitizing HPV-negative HNSCC to IR remains to be explored given that PARP1 and DNA-PkCS bind to unresected stalled DNA replication forks and cooperate to recruit XRCC1 to facilitate double-strand break repair. Here, we show that the combination of the DNA-PK inhibitor NU7441 and the PARP inhibitor olaparib significantly decrease proliferation (61–78%) compared to no reduction with either agent alone (p < 0.001) in both SCC1 and SCC6 cell lines. Adding IR to the combination further decreased cell proliferation (91–92%, p < 0.001) in SCC1 and SCC6. Similar results were observed using long-term colony formation assays [dose enhancement ratio (DER) 2.3–3.2 at 4Gy, p < 0.05]. Reduced cell survival was attributed to increased apoptosis and G2/M cell cycle arrest. Kinomic analysis using tyrosine (PTK) and serine/threonine (STK) arrays reveals that combination treatment results in the most potent inhibition of kinases involved in the CDK and ERK pathways compared to either agent alone. In vivo, a significant delay of tumor growth was observed in UM-SCC1 xenografts receiving IR with olaparib and/or NU7441, which was similar to the cisplatin-IR group. Both regimens were less toxic than cisplatin-IR as assessed by loss of mouse body weight. Taken together, these results demonstrate that the combination of NU7441 and olaparib with IR enhances HPV-negative HNSCC inhibition in both cell culture and in mice, suggesting a potential innovative combination for effectively treating patients with HPV-negative HNSCC. |
| first_indexed | 2024-04-13T14:36:34Z |
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| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T14:36:34Z |
| publishDate | 2020-09-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-f716021e1f6549fb9da39a8bff8d3bda2022-12-22T02:43:02ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-09-011110.3389/fgene.2020.01036573262Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma GrowthLing Zeng0Drexell Hunter Boggs1Chuan Xing2Zhuo Zhang3Joshua C. Anderson4Narendra Wajapeyee5Narendra Wajapeyee6Chris Veale7Markus Bredel8Lewis Z. Shi9James A. Bonner10Christopher D. Willey11Christopher D. Willey12Christopher D. Willey13Christopher D. Willey14Eddy S. Yang15Eddy S. Yang16Eddy S. Yang17Eddy S. Yang18Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesO’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesO’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesO’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesNovel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets that, when inhibited, exhibit potent IR sensitization are PARP1 and DNA-PKcs. However, their cooperation in sensitizing HPV-negative HNSCC to IR remains to be explored given that PARP1 and DNA-PkCS bind to unresected stalled DNA replication forks and cooperate to recruit XRCC1 to facilitate double-strand break repair. Here, we show that the combination of the DNA-PK inhibitor NU7441 and the PARP inhibitor olaparib significantly decrease proliferation (61–78%) compared to no reduction with either agent alone (p < 0.001) in both SCC1 and SCC6 cell lines. Adding IR to the combination further decreased cell proliferation (91–92%, p < 0.001) in SCC1 and SCC6. Similar results were observed using long-term colony formation assays [dose enhancement ratio (DER) 2.3–3.2 at 4Gy, p < 0.05]. Reduced cell survival was attributed to increased apoptosis and G2/M cell cycle arrest. Kinomic analysis using tyrosine (PTK) and serine/threonine (STK) arrays reveals that combination treatment results in the most potent inhibition of kinases involved in the CDK and ERK pathways compared to either agent alone. In vivo, a significant delay of tumor growth was observed in UM-SCC1 xenografts receiving IR with olaparib and/or NU7441, which was similar to the cisplatin-IR group. Both regimens were less toxic than cisplatin-IR as assessed by loss of mouse body weight. Taken together, these results demonstrate that the combination of NU7441 and olaparib with IR enhances HPV-negative HNSCC inhibition in both cell culture and in mice, suggesting a potential innovative combination for effectively treating patients with HPV-negative HNSCC.https://www.frontiersin.org/article/10.3389/fgene.2020.01036/fullDNA repairDNA damagePARP inhibitorsDNA-PK inhibitorsnon-homologous end-joininghomologous recombination |
| spellingShingle | Ling Zeng Drexell Hunter Boggs Chuan Xing Zhuo Zhang Joshua C. Anderson Narendra Wajapeyee Narendra Wajapeyee Chris Veale Markus Bredel Lewis Z. Shi James A. Bonner Christopher D. Willey Christopher D. Willey Christopher D. Willey Christopher D. Willey Eddy S. Yang Eddy S. Yang Eddy S. Yang Eddy S. Yang Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth Frontiers in Genetics DNA repair DNA damage PARP inhibitors DNA-PK inhibitors non-homologous end-joining homologous recombination |
| title | Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth |
| title_full | Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth |
| title_fullStr | Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth |
| title_full_unstemmed | Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth |
| title_short | Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth |
| title_sort | combining parp and dna pk inhibitors with irradiation inhibits hpv negative head and neck cancer squamous carcinoma growth |
| topic | DNA repair DNA damage PARP inhibitors DNA-PK inhibitors non-homologous end-joining homologous recombination |
| url | https://www.frontiersin.org/article/10.3389/fgene.2020.01036/full |
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