Targeting DNA damage response deficiency in the treatment of breast cancer

doi:10.19401/j.cnki.1007-3639.2022.01.008

Abstract

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

CLC Number:

R737.9

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.

Figures/Tables 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