Targeting the DNA repair pathway for breast cancer therapy: Beyond the molecular subtypes - 04/12/23

Doi : 10.1016/j.biopha.2023.115877

Yuting Qu ^a,^g,^{^{1
These authors contributed equally to this work}}, Sisi Qin ^b,^{^{1
These authors contributed equally to this work}}, Zhihui Yang ^a,^g, Zhuolin Li ^c,^g, Qinhao Liang ^a,^g, Ting Long ^d,^g, Weiyun Wang ^e,^g, Dan Zeng ^d,^g, Qing Zhao ^d,^g, Zehua Dai ^g, Qing Ni ^g, Fei Zhao ^f, Wootae Kim ^b,^⁎ , Jing Hou ^g,^⁎
^a Zunyi Medical University, No.6 Xuefu West Road, Zunyi, Guizhou Province, 563006, China
^b Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151 Chungcheongnam-do, Republic of Korea
^c GuiZhou University Medical College, Guiyang, Guizhou Province 550025, China
^d Guizhou Medical University, NO.9 Beijing Road, Guiyang, Guizhou Province 550004, China
^e Guizhou University of Traditional Chinese Medicine, NO.50 Shi Dong Road, Guiyang, Guizhou Province 550002, China
^f College of Biology, Hunan University, Changsha 410082, China
^g Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, Guizhou Province 550002, China

^⁎Corresponding authors.

Abstract

DNA repair is a vital mechanism in cells that protects against DNA damage caused by internal and external factors. It involves a network of signaling pathways that monitor and transmit damage signals, activating various cellular activities to repair DNA damage and maintain genomic integrity. Dysfunctions in this repair pathway are strongly associated with the development and progression of cancer. However, they also present an opportunity for targeted therapy in breast cancer. Extensive research has focused on developing inhibitors that play a crucial role in the signaling pathway of DNA repair, particularly due to the remarkable success of PARP1 inhibitors (PARPis) in treating breast cancer patients with BRCA1/2 mutations. In this review, we summarize the current research progress and clinical implementation of BRCA and BRCAness in targeted treatments for the DNA repair pathway. Additionally, we present advancements in diverse inhibitors of DNA repair, both as individual and combined approaches, for treating breast cancer. We also discuss the clinical application of DNA repair-targeted therapy for breast cancer, including the rationale, indications, and summarized clinical data for patients with different breast cancer subtypes. We assess their influence on cancer progression, survival rates, and major adverse reactions. Last, we anticipate forthcoming advancements in targeted therapy for cancer treatment and emphasize prospective areas of development.

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Graphical Abstract

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Highlights

●	Molecular subtypes-based therapies have limitations for precise treatments of breast cancer.
●	Targeted treatment for breast cancer patients with the theory of synthetic lethality is state-of-the-art concept.
●	BRCAness related gene mutations lead to HR functional defects, and BRCAness patients can benefit from PARP inhibitor therapy.
●	Research on expanding targeted drug therapy for different DDR Pathways.

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Keywords : Breast cancer, DNA damage, BRCA1/2 mutation, PARP inhibitor, BRCAness