DNA damage response inhibitors: An avenue for TNBC treatment

Abstract

The DNA damage response (DDR) is critical for the maintenance of genomic stability by sensing DNA damage, regulating cell cycle and initiating DNA repair. Drugs targeting DDR pathways have been increasingly exploited in treating various tumors. Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive tumor with constitutive activation of oncogenes, inducing replication stress and DNA damage, which require the DDR for survival. In addition, emerging studies have demonstrated that TNBC harbors aberrant genetic alterations in DDR pathways, such as a high frequency of p53 dysfunction and BRCA1/2 mutations. DDR alterations force TNBC to rely on the existing DDR pathways for survival, and make TNBC particularly sensitive to specific DDR inhibitors, such as high sensitivity of TNBC with BRCA1/2 mutations to PARP inhibitors. This review first and comprehensively covers the current status of the development of DDR inhibitors and discusses the mechanism of targeting the DDR in TNBC. Preclinical and clinical studies on inhibitors of the ATR-CHK1-WEE1 pathway and PARP inhibitors, the most studied inhibitors, and some other DDR inhibitors as monotherapy or combination therapy in TNBC are summarized. We also highlight the possible predictive biomarkers for these DDR inhibitors and their potential combination strategies with chemotherapy, radiotherapy or other targeted agents to optimize the efficacy of DDR inhibitors in TNBC treatment. In conclusion, this review discussed the recent considerations related to the use of DDR inhibitors for TNBC and provides a perspective to address future directions and potential therapeutic strategies for patients with TNBC.