Research progress in targeting homologous recombination repair for tumor therapy
10.16438/j.0513-4870.2020-0624
- VernacularTitle:靶向同源重组修复的抗肿瘤研究进展
- Author:
Zhen-xing ZHONG
1
;
Xin PENG
1
,
2
;
De-xin KONG
1
Author Information
1. School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
2. Department of Systems Biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Publication Type:Research Article
- Keywords:
homologous recombination repair;
poly(ADP-ribose) polymerase inhibitor;
antitumor;
synthetic lethality;
DNA double-strand breaks
- From:
Acta Pharmaceutica Sinica
2020;55(11):2535-2548
- CountryChina
- Language:Chinese
-
Abstract:
Applying poly(ADP-ribose) polymerase inhibitors (PARPi) to the treatment of cancers with homologous recombination deficiency (HRDness) has been a great advance in the field of molecular therapeutics. However, in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy. Therefore, targeting homologous recombination (HR) repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of "chemical HRDness". HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity. In addition to directly targeting HR components, modulation of regulatory pathways controlling HR repair is effective in achieving the "HRDness" phenotype; this includes modulation of the cell cycle checkpoint regulatory pathway, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, the chromatin remodeling pathway, etc. Targeting HR repair can not only result in "synthetic lethality" when combined with PARPi, but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy. In this review we describe the HR repair pathway and its regulatory pathways, summarize the preclinical and clinical outcomes of targeting HR repair, discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.
