Sugantha Priya Elayapillai , Samrita Dogra , James Lausen , Madison Parker , Amy Kennedy , Doris M. Benbrook , Katherine M. Moxley , Bethany N. Hannafon
{"title":"ATR 抑制增加了对 PARP 介导的 DNA 修复的依赖,揭示了一种更好的宫颈癌治疗策略。","authors":"Sugantha Priya Elayapillai , Samrita Dogra , James Lausen , Madison Parker , Amy Kennedy , Doris M. Benbrook , Katherine M. Moxley , Bethany N. Hannafon","doi":"10.1016/j.ygyno.2024.10.009","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.</div></div><div><h3>Methods</h3><div>The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.</div></div><div><h3>Results</h3><div>Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.</div></div><div><h3>Conclusions</h3><div>Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"191 ","pages":"Pages 182-193"},"PeriodicalIF":4.5000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer\",\"authors\":\"Sugantha Priya Elayapillai , Samrita Dogra , James Lausen , Madison Parker , Amy Kennedy , Doris M. Benbrook , Katherine M. Moxley , Bethany N. Hannafon\",\"doi\":\"10.1016/j.ygyno.2024.10.009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.</div></div><div><h3>Methods</h3><div>The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.</div></div><div><h3>Results</h3><div>Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.</div></div><div><h3>Conclusions</h3><div>Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.</div></div>\",\"PeriodicalId\":12853,\"journal\":{\"name\":\"Gynecologic oncology\",\"volume\":\"191 \",\"pages\":\"Pages 182-193\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gynecologic oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0090825824011594\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OBSTETRICS & GYNECOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gynecologic oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0090825824011594","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}
ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer
Objective
Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.
Methods
The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.
Results
Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.
Conclusions
Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.
期刊介绍:
Gynecologic Oncology, an international journal, is devoted to the publication of clinical and investigative articles that concern tumors of the female reproductive tract. Investigations relating to the etiology, diagnosis, and treatment of female cancers, as well as research from any of the disciplines related to this field of interest, are published.
Research Areas Include:
• Cell and molecular biology
• Chemotherapy
• Cytology
• Endocrinology
• Epidemiology
• Genetics
• Gynecologic surgery
• Immunology
• Pathology
• Radiotherapy