DNA损伤应答缺陷作为乳腺癌治疗靶点的研究进展

doi:10.19401/j.cnki.1007-3639.2022.01.008

摘要/Abstract

摘要：

DNA损伤应答（DNA damage response,DDR）缺陷是近年来乳腺癌治疗研究的热门靶点之一。DDR通路负责DNA损伤后的识别、信号转导和修复,其功能异常可导致细胞的凋亡或基因组不稳定性的增加。目前进入临床研究阶段的乳腺癌DDR靶向药物主要包括多聚腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase,PARP]抑制剂、ATM抑制剂、CHEK1抑制剂、ATR抑制剂及WEE1抑制剂等。主要从DDR缺陷的概念、以DDR作为靶点的基本原理、DDR各类靶向药物的临床研究现状及其在临床应用中的难点与挑战等方面展开综述。

关键词: DNA损伤应答, 同源重组修复, 乳腺癌, 治疗

Abstract:

DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer in recent years. The DDR pathway is essential for the identification, signal transduction and repair of DNA damage. Its dysfunction may lead to cell apoptosis or genomic instability. Poly (ADP-ribose) polymerase (PARP) inhibitors, ATM inhibitors, CHEK1 inhibitors, ATR inhibitors and WEE1 inhibitors are DDR drugs that already in the clinical development for treating breast cancer. In this review, we introduced the concept of DDR deficiency, the rationale and research advances in DDR-targeted drugs, and discussed the challenges in its clinical applications.

Key words: DNA damage response, Homologous recombination, Breast cancer, Treatment

中图分类号:

R737.9

金奕滋, 林明曦, 张剑. DNA损伤应答缺陷作为乳腺癌治疗靶点的研究进展[J]. 中国癌症杂志, 2022, 32(1): 61-67.

JIN Yizi, LIN Mingxi, ZHANG Jian. Targeting DNA damage response deficiency in the treatment of breast cancer[J]. China Oncology, 2022, 32(1): 61-67.

图/表 2

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Target	Role in DDR	Agent	Clinical trial number (phase)	Regimens in clinical trial
ATM	Checkpoint signaling	AZD-0156	NCT02588105 (Ⅰ)	Monotherapy/combination with olaparib or chemotherapy or other
ATR	Facilitates the stabilization of replication fork and restart	Ceralasertib (AZD-6738)	NCT03740893 (Ⅱ)	Monotherapy; neoadjuvant and adjuvant
			NCT04090567 (Ⅱ)	Combination with olaparib
			NCT03182634 (Ⅱ)	Combination with olaparib
			NCT04704661 (Ⅰ)	Combination with DS-8201a
			NCT03330847 (Ⅱ)	Combination with olaparib
CHEK1	Downstream effector kinase of ATR	Prexasertib (LY2606368)	NCT02203513 (Ⅱ)	Monotherapy
			NCT04032080 (Ⅱ)	Combination with DNA-PK inhibitor
			NCT02124148 (Ⅰ)	Combination with chemotherapy/targeted therapy
			NCT03495323 (Ⅰ)	Combination with PD-L1 inhibitor
WEE1	Checkpoint kinase negatively regulates entry into mitosis	Adavosertib (AZD-1775)	NCT03330847 (Ⅱ)	Combination with olaparib
			NCT03012477 (Ⅱ)	Combination with chemotherapy
			NCT02482311 (Ⅰ)	Monotherapy
			NCT02465060 (Ⅱ)	Monotherapy

Agent	Study (phase)	Regimen	Clinical setting
PARP inhibitors
Olaparib	PETREMAC NCT02624973 (Ⅱ)	Monotherapy	Neoadjuvant treatment for operable TNBC
	NCT02484404 (Ⅰ/Ⅱ)	Combination with PD-L1 inhibitor	Advanced/recurrent TNBC
	NCT02498613 (Ⅱ)	Combination with VEGFR inhibitor	Advanced/metastatic TNBC
	DORA NCT03167619 (Ⅱ)	Combination with PD-L1 inhibitor	Advanced/metastatic TNBC
Veliparib	NCT01306032 (Ⅱ)	Combination with chemotherapy	Metastatic TNBC
	BrighTNess NCT02032277 (Ⅲ)	Combination with chemotherapy	Neoadjuvant treatment for operable TNBC
Niraparib	KEYNOTE-162 NCT02657889 (Ⅱ)	Combination with PD-1 inhibitor	Advanced/metastatic TNBC
Talazoparib	NCT03901469 (Ⅱ)	Combination with BET inhibitor	Advanced/metastatic TNBC
ATR inhibitor
Ceralasertib (AZD-6738)	NCT03740893 (Ⅱ)	Monotherapy	Neoadjuvant and adjuvant treatment for TNBC
	NCT03330847 (Ⅱ)	Combination with olaparib	Metastatic TNBC
CHEK1 inhibitor
Prexasertib (LY2606368)+LY3023414	NCT04032080 (Ⅱ)	Combination with DNA-PK inhibitor	Metastatic TNBC
	NCT02203513 (Ⅱ)	Monotherapy	Advanced TNBC
WEE1 inhibitor
Adavosertib (AZD-1775)	NCT03012477 (Ⅱ)	Combination with chemotherapy	Metastatic TNBC
	NCT02482311 (Ⅰ)	Monotherapy	Advanced/metastatic TNBC