bmn-673 and Triple-Negative-Breast-Neoplasms

Advanced triple negative breast cancer (TNBC) is an aggressive disease (high probability of visceral metastasis) with poor outcome. Triple negative breast cancer is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2), high histologic grade, and high mitotic rate. Chemotherapy remains the primary systemic treatment, with international guidelines supporting the use of single-agent taxanes (with or without bevacizumab) or anthracyclines as first-line therapy, with a median overall survival of approximately 18 months or less. Given the suboptimal outcomes with chemotherapy, new targeted therapies for advanced TNBC are urgently needed. This review summarizes the current status of treatment, and future challenges of using new treatment options for advanced TNBC, such as poly-adenosine-diphosphate-ribose-polymerase inhibitors (olaparib and talazoparib) and immune checkpoint inhibitors (eg atezolizumab) as monotherapy or in combination with chemotherapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Humans; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms

The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC.. Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed.. Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose).. Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated.. NCT03499353.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Germ-Line Mutation; Humans; Neoadjuvant Therapy; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; Triple Negative Breast Neoplasms

Talazoparib has demonstrated efficacy in patients with. Eligibility included 1 cm or larger invasive tumor and g. Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353).

Topics: Administration, Oral; Adult; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Germ-Line Mutation; Humans; Medication Adherence; Middle Aged; Neoadjuvant Therapy; Phthalazines; Pilot Projects; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms

Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination.. To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes.. In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021.. All patients in phases 1b and 2 received avelumab plus talazoparib.. The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers.. A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]).. This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations.. ClinicalTrials.gov Identifier: NCT03330405.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Immunotherapy; Lung Neoplasms; Male; Middle Aged; Poly(ADP-ribose) Polymerase Inhibitors; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Triple Negative Breast Neoplasms

Talazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative, locally advanced or metastatic breast cancer (LA/mBC), with approval based on the EMBRACA trial. To date, there are no published data on talazoparib use in the real-world United States (USA) setting.. Characteristics, treatment patterns, and clinical outcomes of real-world US patients with gBRCAm HER2-negative LA/mBC treated with talazoparib monotherapy were collected via retrospective chart review and summarized using descriptive statistics.. Among 84 eligible patients, 35.7% had hormone receptor-positive tumors and 64.3% had triple-negative LA/mBC (TNBC). At talazoparib initiation, 29.8% had ECOG PS of ≥2 and 19.0% had brain metastasis. Mutations in gBRCA1 or 2 were detected among 64.3% and 35.7% of patients, respectively. Talazoparib was given as 1st-line therapy in 14.3% of patients, 2nd-line in 40.5%, and 3rd- or 4th-line in 45.2%. Median time to talazoparib treatment failure was 8.5 months (95% CI, 8.0-9.7), median progression-free survival was 8.7 months (95% CI, 8.0-9.9), the median time from initiation to chemotherapy was 12.2 months (95% CI, 10.5-20.1), and the overall response rate was 63.1%. No differences in clinical outcomes were observed between patients with HR-positive/HER2-negative LA/mBC and patients with TNBC by using unadjusted statistical comparisons. Brain metastasis and ECOG PS ≥2 at talazoparib initiation were associated with treatment failure and progression or mortality.. Overall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.

Topics: Adult; Brain Neoplasms; Breast Neoplasms; Female; Humans; Retrospective Studies; Triple Negative Breast Neoplasms; United States

The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound

Topics: Antineoplastic Agents; BRCA1 Protein; Cell Cycle Proteins; Cell Line, Tumor; Homologous Recombination; Humans; Nuclear Proteins; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinazolinones; Synthetic Lethal Mutations; Transcription Factors; Triple Negative Breast Neoplasms

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cell death by inhibiting the repair of DNA strand breaks binding to PARP and regulate immune cells functions. Toll-like receptors (TLRs) mediate the tumor microenvironment through the modulation of proinflammatory cytokines and chemokines. In this context, this study addressed the relationship between the efficacy of talazoparib (TAL) as a PARPi and the activation of TLR3 or TLR9 by Polyinosinic:polycytidylic acid (Poly I:C) or CpG oligodeoxynucleotides (CpG-ODN) stimulation, respectively in triple negative breast cancer (TNBC). TAL alone and the combination of TAL with Poly I:C or CpG-ODN induced cell death were analyzed by water-soluble tetrazolium salt 1 (WST-1), Annexin V analysis, acridine orange staining and mRNA levels of caspase-3 and caspase-8 in HCC1937 and HCC1937-R (TAL resistant) TNBC cells. Additionally, the expression of TLR3, TLR9 and interferon regulatory factor 7 (IRF7) was observed with immunofluorescence staining and western blot analysis. Our findings showed that TAL induced TLR3 and TLR9 activation and acted in synergy with TLR3 and TLR9 agonists in TNBC cells. The stimulation of TLR3 or TLR9 and TAL treatment caused significantly more apoptosis in TNBC cells through the over-expression of caspase-3 and caspase-8. Additionally, TAL combined with Poly I:C or CpG-ODN more increased TLR3, TLR9 and IRF7 protein levels in HCC1937 cells and treatment with TAL and Poly I:C had greater potential for overcoming TAL resistance. In conclusion, the combination of PARPi with TLR agonists may be a new therapeutic combined strategy for the effective immunotherapy of TNBC.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Oligodeoxyribonucleotides; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly I-C; Toll-Like Receptor 3; Toll-Like Receptor 9; Triple Negative Breast Neoplasms; Tumor Microenvironment

Poly (ADP-ribose) polymerase (PARP) inhibitors provide a promising therapeutic strategy for triple-negative breast cancers (TNBCs) with BRCA1/2 mutation. However, acquire resistance mechanisms and genetic alterations limit the clinical efficacy of PARP inhibitors. The aberrant activation of phosphatidylinositol 3-kinase (PI3K) is a significant problem for cancer development and thus the inhibition of PI3K by PI3K inhibitors is a novel targeted therapy in advanced breast cancer. Here, we, for the first time, investigated that the combined inhibition of PARP by Talazoparib (TAL) and PI3K by LY294002 synergistically inhibited proliferation of BRCA1 mutant HCC1937 TNBC cells through apoptosis, G0/G1 arrest, oxidative stress and increased DNA damage compared to drug alone. Additionally, TAL and LY294002 combination could be a promising strategy for overcoming TAL resistance. Co-treatment of TAL with LY294002 considerably suppressed the activation of PI3K, Akt1 and mTOR expression and phosphorylated protein levels in TNBC cells and caused changes in the multiple kinase phosphorylation. Our findings revealed that the dual inhibition of PARP and PI3K might represent an effective therapeutic strategy for TNBC and potentially overcome TAL resistance.

Topics: BRCA1 Protein; Breast Neoplasms; Cell Line, Tumor; Chromones; Female; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms

Talazoparib (TAL) has been effectively used for the treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer. However, acquired resistance to TAL remains a major challenge that impedes the clinical success of TAL treatment. Therefore, elucidation of proteins and pathways that contribute to or are affected by the TAL resistance is urgently needed to improve the treatment response and provide novel treatment strategies for advanced metastatic breast cancers. Herein, we aimed to investigate the altered protein signatures in TAL-resistant triple-negative breast cancer (TNBC) cells by comparing with the TNBC parental cell line via proteomic analysis. After validation of TAL-resistance by WST-1 and Annexin V analysis, two-dimensional gel electrophoresis (2DE)-based proteomic analysis coupled to matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF) mass spectrometry was performed to identify differentially regulated proteins. The findings revealed the identities of 10 differentially regulated proteins in TAL-resistant TNBC cells whose bioinformatic analysis predicted changes in EGF/FGF signaling pathways as well as in the AMPK signaling pathway. In addition, phosphorylation/dephosphorylation dynamics were predicted to be altered in TAL-resistant cells. The proteins identified in this study might be the targets to overcome TAL resistance for the treatment of TNBC.

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Phthalazines; Proteomics; Signal Transduction; Triple Negative Breast Neoplasms

Triple negative breast cancer (TNBC) represents approximately 10-15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.

Topics: BRCA1 Protein; BRCA2 Protein; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; F-Box Proteins; Female; Germ-Line Mutation; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Rad51 Recombinase; Triple Negative Breast Neoplasms

Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase, plays crucial roles in various biological processes, including cell proliferation, DNA damage repair, and intracellular vesicle trafficking. Whether RNF126 is modulated by posttranslational modifications is poorly understood. Here, we show that PARP1 interacts with and poly(ADP)ribosylates RNF126, which then recruits the PAR-binding E3 ubiquitin ligase CHFR to promote ubiquitination and degradation of RNF126. Moreover, RNF126 is required for the activation of ATR-Chk1 signaling induced by either irradiation (IR) or a PARP inhibitor (PARPi), and depletion of RNF126 increases the sensitivity of triple-negative breast cancer (TNBC) cells to PARPi treatment. Our findings suggest that PARPi-mediated upregulation of RNF126 protein stability contributes to TNBC cell resistance to PARPi. Therefore, targeting the E3 ubiquitin ligase RNF126 may be a novel treatment for overcoming the resistance of TNBC cells to PARPi in clinical trials.

Topics: Cell Cycle Proteins; Cell Survival; Humans; Neoplasm Proteins; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly-ADP-Ribose Binding Proteins; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Ubiquitin-Protein Ligases; Up-Regulation

Herein, we investigated efflux pumps-mediated talazoparib-resistance in the treatment of triple-negative breast cancer (TNBC). Furthermore, we produced a novel talazoparib-solid lipid nanoparticles (SLNs) and then explored in vitro therapeutic efficacy of talazoparib-SLNs to overcome talazoparib-resistance in TNBC cells. Talazoparib-SLNs formulation was produced and then characterized. Calcein and Rho-123 were used to analyze the functional activity of drug efflux pumps in these cells. Additionally, RT-PCR, western blot and immunofluorescence analysis were used to detect the messenger RNA, and protein expression level, and cellular localization of the multidrug resistance (MDR1), breast cancer resistance protein (BCRP), and MRP1. We found that talazoparib efflux was mediated by BCRP and MRP1 pumps in TNBC cells. Talazoparib-SLNs could significantly enhance therapeutic efficacy of talazoparib. Furthermore, talazoparib-SLNs were more effective in the suppression of MDR1, BCRP, and MRP1 gene and protein expression levels than talazoparib. Consequently, this study suggests that talazoparib-SLNs formulation represents a promising therapeutic carrier to reverse MDR-mediated resistance in TNBC.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Lipids; Multidrug Resistance-Associated Proteins; Nanoparticles; Neoplasm Proteins; Phthalazines; Triple Negative Breast Neoplasms

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.

Topics: BRCA1 Protein; Cell Line, Tumor; Female; G1 Phase Cell Cycle Checkpoints; Humans; M Phase Cell Cycle Checkpoints; Mutation; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms

In the present work, we report for the first time the therapeutic potential of talazoparib (BMN 673)-SLNs for the treatment of BRCA1 deficient Triple Negative Breast Cancer (TNBC). BMN 673-SLNs were produced by hot-homogenization technique and then characterized.. The cytotoxic and apoptotic effects of BMN 673-SLNs compared with BMN 673 were determined on HCC1937BRCA1-/-, HCC1937-R resistant TNBC and MCF-10A control cell lines. BMN 673- SLNs were found to have reduced particle size (219.5 ± 1.45 nm) and thus more stable (-28.4 ± 2.52 mV) than BMN 673 (1652 ± 2.46 nm and -18.6 ± 0.45 mV) at 4°C.. In vitro cell line studies demonstrated that BMN 673-SLNs showed significant cytotoxic effects on HCC1937 (29.8%) and HCC1937-R cells (35.7%) at 10 nM for 12 days compared with BMN 673 (HCC1937 cells: 34.0% and HCC1937-R cells: 93.8% at 10 nM for 12 days) (p<0.05). Additionally, BMN 673-SLNs (40.1%) reduced the toxicity of BMN 673 (53.1%) on MCF-10A control cells thanks to unique physical properties.. The apoptotic rates in the 10 nM BMN 673-SLNs treatment (88.78% and 85.56%) for 12 days were significantly higher than those in 10 nM BMN 673 (82.6% and 25.86%) for 12 days in HCC1937 and HCC1937-R cells, respectively (p<0.01). Furthermore, these effects were consistent with the findings of colony formation, wound healing and calcein accumulation analysis. In conclusion, the therapeutic potential of BMN 673-SLNs provides a promising chemotherapeutic strategy for the treatment of drugresistant TNBC.

Topics: Antineoplastic Agents; Apoptosis; BRCA1 Protein; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Lipids; Nanoparticles; Phthalazines; Structure-Activity Relationship; Triple Negative Breast Neoplasms; Tumor Cells, Cultured

The purpose of the study was to produce BMN 673 loaded solid lipid nanoparticles (SLNs) to improve its therapeutic index, to minimize toxicity and to overcome homologous recombination (HR)-mediated resistance.. Firstly, BMN 673-SLNs were characterized using Nano Zeta Sizer. After treatment with different concentrations of BMN 673 and BMN 673-SLNs, cell viability of HCC1937. When compared with BMN 673, BMN 673-SLNs showed remarkably a decrease in HCC1937 and HCC1937-R cells with less damage to MCF-10A cells. BMN 673-SLNs significantly induced toxicity through double-stranded DNA breaks, G2/M cell cycle arrest and PARP cleavage in TNBC cells. Additionally, BMN 673-resistance was mediated by miR-107, miR-193b and miR-1255b targeting BRCA1 and RAD51 in HCC1937 and HCC1937-R cells. However, BMN 673-SLNs treatment could overcome HR-mediated resistance in TNBC cells.. As a result, our findings suggest that SLNs formulation strongly provides a synthetic lethal therapeutic potential in BRCA1 mutated sensitive and resistant TNBC cells.

Topics: Antineoplastic Agents; BRCA1 Protein; Cell Cycle Checkpoints; Cell Line, Tumor; DNA Breaks, Double-Stranded; Drug Carriers; Humans; Lipids; Mutation; Nanoparticles; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms

Topics: Acrylonitrile; Aniline Compounds; Animals; BRCA1 Protein; BRCA2 Protein; Cell Line, Tumor; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Humans; Mice; Phosphoinositide-3 Kinase Inhibitors; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Camptothecin; Cell Line, Tumor; DNA Repair; DNA Topoisomerases, Type I; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates; Indoles; Mice; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Synthetic Lethal Mutations; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chromatin; DNA Breaks, Double-Stranded; DNA Methylation; Drug Synergism; Female; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred NOD; Mice, Nude; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays