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
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
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.
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.
