Abstract P5-06-01: Talazoparib antitumor effects in <i>BRCA</i>-deficient breast cancer models
Authors: VT Phan, AA Protter, A Peterson, H Uppal
Journal: Cancer Research (2017)

Abstract Background: BRCA1 and BRCA2 functions are essential for the DNA double-strand break repair process in living cells with DNA damages. Therefore, germline pathogenic mutations in BRCA1/2 increases the risk of developing cancer.1, 2Poly(ADP-ribose) polymerase (PARP) enzymes are proteins responsible for DNA single-strand break repair. Persistent inhibition of PARP-dependent DNA repair in BRCA-deficient breast cancer cells leads to increased DNA damages resulting in cancer cell death. Talazoparib is a novel and potent, orally bioavailable, small molecule PARP inhibitor. Talazoparib's dual mechanism of action inhibits PARP enzyme activity and effectively traps PARP on DNA, preventing DNA repair, resulting in cell death in BRCA1/2-mutated cells.3 In tissue culture studies, talazoparib is more potent at trapping PARP on DNA to induce cancer cell death compared to other PARP inhibitors.4 Previous studies have demonstrated talazoparib inhibited growth in tumors harboring BRCA1/2 gene mutations. In the MX-1 breast cancer model with BRCA1-deficiency, talazoparib inhibited cell growth in vitro and induced regression in solid mouse xenografts.5 Here, we demonstrate antitumor effects of talazoparib monotherapy in a panel of breast cancer cells and patient-derived breast cancer models with pathologic BRCA1/2 mutations. Method: A panel of human breast cancer cell lines was treated with talazoparib to determine its cytotoxic effects. BRCA1/2 mutations status was correlated to talazoparib cytotoxic effects. At the molecular level, BRCA1/2-mutant and wild type breast cancer cell lines were treated with dose-escalating talazoparib to also assess the relationship between PARP-DNA trapping complex formation and treatment response. Patient-derived breast cancer xenograft models were used to assess talazoparib monotherapy on tumorigenesis. Immunohistochemistry assays were performed to determine Ki-67, gH2AX and caspase 3 marker expression following talazoparib treatment. Results: Cytotoxicity was observed in 50% (7/14) cell lines at IC50 values that are achieved in the clinic. BRCA1/2 alterations were detected in 21.4% (3/14) of cell lines sensitive to talazoparib treatment. In 14 patient-derived breast cancer xenograft models selected for this study, 57.1% (8/14) responded to talazoparib monotherapy. Of these, 35.7% had mutations in the BRCA1 (28.6%) and BRCA2 (7.1%) genes. Stable disease was observed in 14.2% (2/14). One stable model had BRCA1 mutations. Tumor regression was observed in 42.8% (6/14) of the models treated with talazoparib monotherapy. Importantly, 66.7% (4/6) of patient-derived breast cancer models that regressed on talazoparib monotherapy had mutations in BRCA1/2 genes. Conclusions: Cytotoxicity was observed with talazoparib monotherapy in breast cancer cell lines and in patient-derived xenograft tumor models harboring BRCA1 or BRCA2 mutations. Our data demonstrate therapeutic potential of talazoparib monotherapy in breast cancer associated with pathologic BRCA1/2 mutations. 1.Couch FJ et al. J Clin Oncol. 2015;33:304-11. 2. Petrucelli N et al. Genet Med. 2010;12:245-59. 3. Wang B et al. J Med Chem. 2016;59:335-57. 4. Murai J et al. Mol Cancer Ther. 2014;13:433-43. 5. Shen Y et al. Clin Cancer Res. 2013;19:5003-15. Citation Format: Phan VT, Protter AA, Peterson A, Uppal H. Talazoparib antitumor effects in BRCA-deficient breast cancer models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-01.