Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recogni...Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways,thereby inducing targeted death of cancerous cells,particularly in cancers with homologous recombination deficiency(HRD).These inhibitors have been approved for the treatment of several cancers,such as ovarian,breast,and pancreatic cancers.Despite their promising therapeutic attributes,developing resistance to PARPi presents a formidable obstacle,curtailing their overall efficacy.This article presents a comprehensive description of the potential mechanisms related to PARPi resistance,an in-depth study of potential strategies to overcome resistance,and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.展开更多
Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)m...Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)modulates the ubiquitination of growth-and invasion-related factors in lung cancer,colorectal cancer,and osteosarcoma.The function of FBXW11 in PARPi therapy is still ambiguous.In this study,RNA sequencing(RNA-seq)showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi.FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer(HGSOC)tissues,and low levels of FBXW11 were associated with shorter overall survival(OS)and progression-free survival(PFS)in HGSOC patients.Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi,while knocking down FBXW11 made it less sensitive.The four-dimensional(4D)label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11(S100A11)and promoted its degradation through ubiquitination.The increased degradation of S100A11 led to less efficient DNA damage repair,which in turn contributed to increased PARPi-induced DNA damage.The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models.In summary,our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.展开更多
Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway c...Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining(NHEJ)-mediated DSB repair pathway that rejoins DSB ends.New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination(HR)signaling.This review focuses on the up-and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair,which in turn promotes the sensitivity of poly(ADP-ribose)polymerase inhibitor(PARPi)in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.展开更多
Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line tre...Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line treatment are frequent.For many patients,however,responses are suboptimal or short-lived.Over the last several years,multiple new classes of agents targeting DNA damage response(DDR)mechanisms have advanced through clinical development.In this review,we explore the preclinical rationale for the use of ATR inhibitors,CHK1 inhibitors,and WEE1 inhibitors,emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer.We also present an overview of the clinical development of the leading drugs in each of these classes,emphasizing the rationale for monotherapy and combination therapy approaches.展开更多
基金supported by the Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences(No.25-LZIHPS-03)the Regional Innovation System&Education(RISE)program through the Chungbuk Regional Innovation System&Education Center,funded by the Ministry of Education(MOE)and the Chungcheongbuk-do,Republic of Korea(No.2025-RISE-11-014-03).
文摘Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways,thereby inducing targeted death of cancerous cells,particularly in cancers with homologous recombination deficiency(HRD).These inhibitors have been approved for the treatment of several cancers,such as ovarian,breast,and pancreatic cancers.Despite their promising therapeutic attributes,developing resistance to PARPi presents a formidable obstacle,curtailing their overall efficacy.This article presents a comprehensive description of the potential mechanisms related to PARPi resistance,an in-depth study of potential strategies to overcome resistance,and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81972440 and 82002740)the Natural Science Foundation of Shaanxi Province,China(Grant No.:2024JC-ZDXM-52).
文摘Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)modulates the ubiquitination of growth-and invasion-related factors in lung cancer,colorectal cancer,and osteosarcoma.The function of FBXW11 in PARPi therapy is still ambiguous.In this study,RNA sequencing(RNA-seq)showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi.FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer(HGSOC)tissues,and low levels of FBXW11 were associated with shorter overall survival(OS)and progression-free survival(PFS)in HGSOC patients.Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi,while knocking down FBXW11 made it less sensitive.The four-dimensional(4D)label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11(S100A11)and promoted its degradation through ubiquitination.The increased degradation of S100A11 led to less efficient DNA damage repair,which in turn contributed to increased PARPi-induced DNA damage.The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models.In summary,our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.
文摘Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining(NHEJ)-mediated DSB repair pathway that rejoins DSB ends.New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination(HR)signaling.This review focuses on the up-and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair,which in turn promotes the sensitivity of poly(ADP-ribose)polymerase inhibitor(PARPi)in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.
基金Bouberhan S has accepted funds from ImmunoGen for consulting,not directly related to this review.The funders had no role in the design of this paper,the interpretation of data,or the writing of the manuscript.Bar-Peled L is a founder and consultant and holds privately held equity in Scorpion Therapeutics.Bar-Peled L was supported by grants from the NCI(CA215249)Damon Runyon Cancer Research Foundation,AACR(19-20-45-BARP)Mary Kay Ash Foundation,LUNGevity,V Foundation,Melanoma Research Foundation,American Cancer Society,and the Ludwig Cancer Center.Rueda BR is funded in part by the Nile Albright Research Foundation and the Vincent Memorial Hospital Research Foundation.
文摘Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line treatment are frequent.For many patients,however,responses are suboptimal or short-lived.Over the last several years,multiple new classes of agents targeting DNA damage response(DDR)mechanisms have advanced through clinical development.In this review,we explore the preclinical rationale for the use of ATR inhibitors,CHK1 inhibitors,and WEE1 inhibitors,emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer.We also present an overview of the clinical development of the leading drugs in each of these classes,emphasizing the rationale for monotherapy and combination therapy approaches.
