Poly(ADP-ribose) Polymerase Inhibitor Talazoparib Inhibits DNA Damage Repair in Breast Cancer Cell Lines With or Without BRCA1/2 Mutation.
Talazoparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in patients with germline BRCA1/2-mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. Although PARP inhibitor sensitivity has traditionally been attributed to synthetic lethality in tumors with BRCA1/2 mutations or homologous recombination repair deficiency, emerging evidence indicates that clinical and preclinical activity may extend to selected tumors beyond those harboring germline BRCA1/2 mutations. This study investigated the mechanism underlying talazoparib efficacy in both BRCA1/2-mutant and BRCA1/2 wild-type breast cancer cells.
Twenty-one breast cancer cell lines, including both BRCA-1/2-mutant and wild-type cells, were treated with talazoparib, and the effects of the treatment on cell proliferation, cell cycle progression, DNA damage accumulation, and apoptosis were evaluated.
Talazoparib demonstrated antiproliferative effects in BRCA1/2-mutant and wild-type cells in a long-term culture system, as assessed by colony formation assays. Accumulation of single-stranded and double-stranded DNA damage was observed in talazoparib-sensitive cell lines, as indicated by phosphorylated RPA and γ-H2AX, respectively. This was accompanied by G2/M arrest and subsequent apoptosis, as evidenced by cleaved caspase-3 expression and Annexin V staining. Abnormal mitotic nuclei were observed in talazoparib-sensitive cell lines, which also exhibited potent and sustained PARP1 trapping on chromatin.
Talazoparib exerts anti-tumor effects in BRCA1/2-mutant and wild-type breast cancer cells by promoting the formation of abnormal mitotic nuclei and inducing apoptosis in sensitive cells. Our findings support the potential therapeutic application of talazoparib beyond its current indications for BRCA1/2-mutant tumors.
Twenty-one breast cancer cell lines, including both BRCA-1/2-mutant and wild-type cells, were treated with talazoparib, and the effects of the treatment on cell proliferation, cell cycle progression, DNA damage accumulation, and apoptosis were evaluated.
Talazoparib demonstrated antiproliferative effects in BRCA1/2-mutant and wild-type cells in a long-term culture system, as assessed by colony formation assays. Accumulation of single-stranded and double-stranded DNA damage was observed in talazoparib-sensitive cell lines, as indicated by phosphorylated RPA and γ-H2AX, respectively. This was accompanied by G2/M arrest and subsequent apoptosis, as evidenced by cleaved caspase-3 expression and Annexin V staining. Abnormal mitotic nuclei were observed in talazoparib-sensitive cell lines, which also exhibited potent and sustained PARP1 trapping on chromatin.
Talazoparib exerts anti-tumor effects in BRCA1/2-mutant and wild-type breast cancer cells by promoting the formation of abnormal mitotic nuclei and inducing apoptosis in sensitive cells. Our findings support the potential therapeutic application of talazoparib beyond its current indications for BRCA1/2-mutant tumors.
Authors
Lee Lee, Lee Lee, Min Min, Ham Ham, Moon Moon, Kim Kim, Hwang Hwang, Noh Noh, Lee Lee, Park Park, Koh Koh, Park Park, Lee Lee, Im Im
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