Triumphs and challenges in exploiting poly(ADP-ribose) polymerase inhibition to combat triple-negative breast cancer.
Jonathan WootenNicole MavingireKatherine DamarAndrea L PerezEileen J BrantleyPublished in: Journal of cellular physiology (2023)
Poly(ADP-ribose) polymerase 1 (PARP1) regulates a myriad of DNA repair mechanisms to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) confer synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Patients with triple-negative breast cancer (TNBC) fail to respond to most targeted therapies because their tumors lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Certain patients with TNBC harbor mutations in HR mediators such as breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), enabling them to respond to PARPi. PARPi exploits the synthetic lethality of BRCA-mutant cells. However, de novo and acquired PARPi resistance frequently ensue. In this review, we discuss the roles of PARP in mediating DNA repair processes in breast epithelial cells, mechanisms of PARPi resistance in TNBC, and recent advances in the development of agents designed to overcome PARPi resistance in TNBC.
Keyphrases
- dna repair
- dna damage
- estrogen receptor
- epidermal growth factor receptor
- breast cancer risk
- dna damage response
- copy number
- oxidative stress
- endothelial cells
- genome wide
- tyrosine kinase
- induced apoptosis
- advanced non small cell lung cancer
- poor prognosis
- dna methylation
- cell cycle arrest
- signaling pathway
- transcription factor
- childhood cancer