BMN 673 (talazoparib): A potent PARP inhibitor for triple negative breast cancer with different genetic profile

Abstract

The objective of the present study was to elucidate the effect of BMN 673 (talozoparib) on BRCA1 mutant (HCC1937) and wild-type (MDA-MB-231) triple negative breast cancer (TNBC). The in vitro cytotoxicity results indicated that BMN 673 had considerable inhibitory effects on HCC1937 and MDA-MB-231 cell lines by inducing apoptosis, multicaspase activity, G2/M arrest, and altering the expression levels of apoptosis-related genes (P < 0.01). Additionally, BMN 673 indicated no toxicity on MCF-10A control cells until a certain concentration and incubation time.However, BMN 673, a novel and selective poly ADP ribose polymerase inhibitor, was more potent in TNBC cells bearing BRCA1 mutant than those with wild-type BRCA1.In conclusion, our study, for the first time, demonstrated a molecular mechanism of the induction of apoptosis by BMN 673 in TNBC with different genetic profile.However, further investigations regarding the exact molecular mechanisms underlying BMN 673-inducing apoptotic death and gene-cell line associations are required. K E Y W O R D S apoptotic death, BMN 673 (talozoparib), BRCA, triple negative breast cancer J Biochem Mol Toxicol. 2019;33:e22286. wileyonlinelibrary.com/journal/jbt Abbreviations: dsDNAs, DNA double-strand breaks; HR, homologous recombination; PARP, poly ADP ribose polymerase; TN, triple negative; TNBC, triple negative breast cancer. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article.

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

“…Moreover, although predominantly targeted to BRCA -mutant cancers, PARPi treatment for non- BRCA -mutant cancers is also emerging in the clinic 1 . Indeed, talazoparib has been shown to induce considerable in vitro cytotoxicity regardless of BRCA1 mutation status, although it is still more potent in BRCA1 mutant tumor cells 61 . Moreover, a preclinical study reported that talazoparib-induced DNA damage and STING activation independent of BRCA mutations in murine models of ovarian and colon cancers 62 .…”

The synergistic proapoptotic effect of PARP-1 and HDAC inhibition in cutaneous T-cell lymphoma is mediated via Blimp-1

“…We have shown that talazoparib arrested the cell cycle of lymphoma cells in G2/M because of upregulation of p53 and p21, which is consistent with previously published data obtained in breast cancer cell lines. 31 PARP inhibition is not always sufficient to cause cell death, 32 and the search for efficient combinations is ongoing. Previous studies in chronic lymphocytic leukemia showed that the activity of talazoparib is independent on the presence of WT p53 or complete loss of p53, indicating the importance of the other mechanism of action of PARPi in leukemia and lymphomas.…”

Triumphs and challenges in exploiting poly(ADP‐ribose) polymerase inhibition to combat triple‐negative breast cancer

“…More recent discovery efforts for PARPi led to olaparib and talazoparib, which demonstrate utility in gBRCAm‐associated breast tumors, and this enabled their approval in 2018 (Fong et al, 2009; Guney Eskiler et al, 2019). In a recent study, different PARPi were evaluated in 12 breast cancer cell lines with and without gBRCAm; five of the eight TNBC cell lines were susceptible to PARPi, regardless of their BRCA status (Keung et al, 2020).…”