Triple-negative breast cancer therapeutic resistance: Where is the Achilles' heel?

• Published in: Cancer letters 2021-01, Vol.497, p.100-111
• Main Authors: Bai, Xupeng, Ni, Jie, Beretov, Julia, Graham, Peter, Li, Yong
• Format: Article
• Language: English
• Subjects: Androgens; Animals; Antineoplastic Agents - therapeutic use; Antioxidants; Biosynthesis; Breast cancer; Cancer therapies; Cell cycle; Chemotherapy; Clinical trial; Clinical trials; Cytochrome; Deoxyribonucleic acid; DNA; DNA damage; DNA methylation; DNA repair; Drug development; Drug Resistance, Neoplasm; Drugs; Enzymes; Female; Growth factors; Humans; Immunotherapy; Kinases; Medical prognosis; Metabolism; Metastases; Molecular Targeted Therapy; Proteins; Quality of life; Radiation therapy; Targeted drug; Therapeutic resistance; TNBC; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor microenvironment
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.10.016

Triple-negative breast cancer (TNBC) shows a higher response rate to systemic therapy compared with other breast cancer subtypes. However, the tumor differentiation of TNBC is poorer, with an early tendency to metastasis and a higher recurrence rate. Relapsed and metastatic TNBCs usually progress more rapidly, showing strong resistance to chemotherapy and radiotherapy. Due to the lack of combinatorial targeted drugs, alternative treatments fail to improve these patient's prognosis and the quality of life. Finding the Achilles' heel of TNBC is critical for patients with advanced TNBC. Here, we summarize the latest advances in the mechanisms underlying TNBC therapeutic resistance, consider how these mechanisms may affect the development and utilization of TNBC targeted drugs, and discuss the rationale of relevant signals as therapeutic targets. Also, we review the clinical trials registered in ClinicalTrial.gov for TNBC patients, which comprehensively reveals current research and development of novel TNBC targeted drugs and future trends. •DNA repair is closely associated with TNBC therapeutic resistance.•Tumor microenvironment contributes greatly to the malignancy of TNBC.•PI3Kα-specific and ATK inhibitors demonstrate promising efficacy against TNBC.•PARP1 and AR inhibitors are effective for TNBC under the guidance of gene subtyping.•Immunotherapy is the current development trend of targeted drugs against TNBC.