Targeting replication stress in cancer therapy

被引：177

作者：

da Costa, Alexandre Andre B. A. ^{[1
]}

Chowdhury, Dipanjan ^{[1
]}

Shapiro, Geoffrey I. ^{[2
]}

D'Andrea, Alan D. ^{[1
,3
]}

Konstantinopoulos, Panagiotis A. ^{[2
]}

机构：

[1] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02115 USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2023年 / 22卷 / 01期

关键词：

WEE1 INHIBITOR AZD1775; DNA-DAMAGE RESPONSE; CHECKPOINT KINASE 1; MYELOID-LEUKEMIA CELLS; SEROUS OVARIAN-CANCER; ADVANCED SOLID TUMORS; I DOSE-ESCALATION; PHASE-I; CHK1; INHIBITOR; ATR INHIBITOR;

D O I：

10.1038/s41573-022-00558-5

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.

引用

页码：38 / 58

页数：21

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