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The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer.
Wilson AJ, Stubbs M, Liu P, Ruggeri B, Khabele D
(2018) Gynecol Oncol 149: 575-584
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, BRCA1 Protein, Carcinoma, Ovarian Epithelial, Cell Cycle Proteins, Cell Line, Tumor, Down-Regulation, Drug Synergism, Female, Homologous Recombination, Humans, Indoles, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasms, Glandular and Epithelial, Nuclear Proteins, Organic Chemicals, Ovarian Neoplasms, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Transcription Factors, Xenograft Model Antitumor Assays
Show Abstract · Added March 3, 2020
OBJECTIVE - Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage.
METHODS - HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1.289+BRCA1) were treated with BRD4-targeting siRNA, novel (INB054329, INCB057643) and established (JQ1) BET inhibitors (BETi) and PARPi (olaparib, rucaparib). Cell growth and viability were assessed by sulforhodamine B assays in vitro, and in SKOV-3 and ovarian cancer patient-derived xenografts in vivo. DNA damage and repair (pH2AX, RAD51 and BRCA1 foci formation, and DRGFP HR reporter activity), apoptosis markers (cleaved PARP, cleaved caspase-3, Bax) and proliferation markers (PCNA, Ki67) were assessed by immunofluorescence and western blot.
RESULTS - In cultured cells, inhibition of BRD4 by siRNA or INCB054329 reduced expression and function of BRCA1 and RAD51, reduced HR reporter activity, and sensitized the cells to olaparib-induced growth inhibition, DNA damage induction and apoptosis. Synergy was observed between all BETi tested and PARPi. INCB054329 and olaparib also co-operatively inhibited xenograft tumor growth, accompanied by reduced BRCA1 expression and proliferation, and increased apoptosis and DNA damage.
CONCLUSIONS - These results provide strong rationale for using BETi to extend therapeutic efficacy of PARPi to HR-proficient ovarian tumors and could benefit a substantial number of women diagnosed with this devastating disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks.
Dungrawala H, Bhat KP, Le Meur R, Chazin WJ, Ding X, Sharan SK, Wessel SR, Sathe AA, Zhao R, Cortez D
(2017) Mol Cell 67: 374-386.e5
MeSH Terms: A549 Cells, Animals, BRCA2 Protein, CRISPR-Cas Systems, DNA Breaks, Double-Stranded, DNA Repair, DNA, Neoplasm, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Genomic Instability, HEK293 Cells, Humans, Mice, Models, Molecular, Mutation, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Protein Binding, RNA Interference, Rad51 Recombinase, Replication Origin, Transfection
Show Abstract · Added March 24, 2018
RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability.
Copyright © 2017 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L
(2016) Nat Rev Clin Oncol 13: 674-690
MeSH Terms: Androgen Antagonists, BRCA2 Protein, Biomarkers, Tumor, Clinical Trials as Topic, Female, Humans, Immune System, Immunotherapy, Mitogen-Activated Protein Kinases, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells, Phosphoinositide-3 Kinase Inhibitors, Poly(ADP-ribose) Polymerase Inhibitors, Prognosis, Triple Negative Breast Neoplasms, Ubiquitin-Protein Ligases
Show Abstract · Added April 6, 2017
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.
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Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.
Leichman L, Groshen S, O'Neil BH, Messersmith W, Berlin J, Chan E, Leichman CG, Cohen SJ, Cohen D, Lenz HJ, Gold P, Boman B, Fielding A, Locker G, Cason RC, Hamilton SR, Hochster HS
(2016) Oncologist 21: 172-7
MeSH Terms: Adult, Aged, Colorectal Neoplasms, DNA Methylation, DNA Mismatch Repair, Disease-Free Survival, Female, Humans, Male, Microsatellite Instability, Middle Aged, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors
Show Abstract · Added May 7, 2016
BACKGROUND - Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality.
METHODS - This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS).
RESULTS - Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group.
CONCLUSION - Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study.
IMPLICATIONS FOR PRACTICE - Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.
©AlphaMed Press.
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14 MeSH Terms
Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.
Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, Shah B, Sharma S, Chang JC, Melnick AM, Hiebert S, Bhalla KN
(2014) Oncotarget 5: 5637-50
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cell Line, Tumor, Checkpoint Kinase 1, Cisplatin, DNA Damage, Drug Synergism, Enzyme Inhibitors, Female, Gene Knockdown Techniques, HSP90 Heat-Shock Proteins, HeLa Cells, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Indoles, MCF-7 Cells, Mice, Panobinostat, Poly(ADP-ribose) Polymerase Inhibitors, Protein Kinases, Reactive Oxygen Species, Triple Negative Breast Neoplasms, Vorinostat, Xenograft Model Antitumor Assays
Show Abstract · Added September 28, 2015
There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.
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28 MeSH Terms
Prospects and challenges for the development of new therapies for Ewing sarcoma.
Grohar PJ, Helman LJ
(2013) Pharmacol Ther 137: 216-24
MeSH Terms: Antineoplastic Agents, Bone Neoplasms, Camptothecin, Clinical Trials as Topic, Dioxoles, Epigenesis, Genetic, Humans, Molecular Targeted Therapy, Poly(ADP-ribose) Polymerase Inhibitors, Sarcoma, Ewing, Somatomedins, Tetrahydroisoquinolines, Trabectedin
Show Abstract · Added September 3, 2013
The Ewing sarcoma family of tumors or Ewing sarcoma (ES) is the second most common malignant bone tumor of childhood. The prognosis for localized Ewing sarcoma has improved through the development of intense multimodal therapy over the past several decades. Unfortunately, patients with recurrent or metastatic disease continue to have a poor prognosis. Therefore, a number of complementary approaches are being developed in both the preclinical and clinical arenas to improve these outcomes. In this review, we will discuss efforts to directly target the biologic drivers of this disease and relate these efforts to the experience with several different agents both in the clinic and under development. We will review the data for compounds that have shown excellent activity in the clinic, such as the camptothecins, and summarize the biological data that supports this activity. In addition, we will review the clinical experience with IGF1 targeted agents, ET-743 and epigenetically targeted therapies, the substantial amount of literature that supports their activity in Ewing sarcoma and the challenges remaining translating these therapies to the clinic. Finally, we will highlight recent work aimed at directly targeting the EWS-FLI1 transcription factor with small molecules in Ewing tumors.
Copyright © 2012 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-Ribose) polymerase inhibition.
Yang ES, Nowsheen S, Rahman MA, Cook RS, Xia F
(2012) Cancer Res 72: 5547-55
MeSH Terms: Animals, Breast Neoplasms, Cell Nucleus, Cytoplasm, DNA Breaks, Double-Stranded, DNA Repair, Enzyme Inhibitors, Female, Fluorescent Antibody Technique, Humans, MCF-7 Cells, Mice, Poly(ADP-ribose) Polymerase Inhibitors, Protein Transport, Transplantation, Heterologous, Ubiquitin-Protein Ligases
Show Abstract · Added March 27, 2014
PARP inhibitors have gained recent attention due to their highly selective killing of BRCA1/2-mutated and DNA double-strand break (DSB) repair-deficient tumors. Unfortunately, the majority of sporadic breast cancers carry wild-type BRCA1/2 and are proficient in DSB repair. We and others have shown that BRCA1 is a nuclear/cytoplasm shuttling protein that is transiently exported from the nucleus to the cytosol upon various stimuli. Thus, we hypothesized that depletion of nuclear BRCA1 would compromise DSB repair and subsequently render sporadic tumors susceptible to PARP inhibition. Indeed, in human sporadic breast cancer cells with functional BRCA1 and proficient DSB repair, a transient nuclear depletion of BRCA1 and subsequent homologous recombination repair deficit was induced with either truncated BRCA1 or irradiation. This rendered these human sporadic breast cancer cells susceptible to PARP inhibition. These observations were confirmed genetically using mislocated BRCA1 mutants as well as in vivo in mice bearing breast tumor xenografts. These data support the potential strategy of targeting BRCA1 location to convert BRCA1-proficient sporadic tumors to be susceptible to the synthetic lethal combination with PARP inhibitors.
©2012 AACR.
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16 MeSH Terms
Progress in the function and regulation of ADP-Ribosylation.
Hottiger MO, Boothby M, Koch-Nolte F, Lüscher B, Martin NM, Plummer R, Wang ZQ, Ziegler M
(2011) Sci Signal 4: mr5
MeSH Terms: Adenosine Diphosphate, Animals, Congresses as Topic, Energy Metabolism, Enzyme Inhibitors, Humans, NAD, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Sirtuins, Switzerland
Show Abstract · Added March 20, 2014
Adenosine 5'-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD(+)) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this meeting include promising clinical trials with PARP inhibitors and new insights into cell, structural, and developmental biology of ARTs and the (glyco)hydrolase proteins that catalyze de-ADP-ribosylation of mono- or poly-ADP-ribosylated proteins. Moreover, potential links to the NAD-dependent sirtuin family were explored on the basis of a shared dependence on cellular NAD(+) concentrations and the relationship of ADP-ribosylation with intermediary metabolism and cellular energetics.
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11 MeSH Terms
MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers.
Vilar E, Bartnik CM, Stenzel SL, Raskin L, Ahn J, Moreno V, Mukherjee B, Iniesta MD, Morgan MA, Rennert G, Gruber SB
(2011) Cancer Res 71: 2632-42
MeSH Terms: Benzimidazoles, Cell Line, Tumor, Colorectal Neoplasms, DNA Damage, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MRE11 Homologue Protein, Microsatellite Instability, Mutation, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Rad51 Recombinase, Recombination, Genetic
Show Abstract · Added March 5, 2014
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
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19 MeSH Terms
Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair.
Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D
(2010) J Biol Chem 285: 14565-71
MeSH Terms: Blotting, Western, Bone Neoplasms, Cell Survival, DNA Breaks, Double-Stranded, DNA Repair, Fluorescent Antibody Technique, Humans, Intracellular Signaling Peptides and Proteins, Osteosarcoma, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, RNA, Messenger, RNA, Small Interfering, Rad51 Recombinase, Radiation, Ionizing, Recombination, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Thiolester Hydrolases, Tumor Cells, Cultured, Tumor Stem Cell Assay, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added March 5, 2014
DNA damage repair and checkpoint responses prevent genome instability and provide a barrier to the development of cancer. Inherited mutations in DNA damage response (DDR) genes such as those that encode the homologous recombination (HR) proteins BRCA1 and BRCA2 cause cancer predisposition syndromes. PARP inhibitors are an exciting new class of targeted therapy for treating patients with HR repair-defective tumors. In this study, we use an RNAi screen to identify genes that when silenced cause synthetic lethality with the PARP inhibitor AZD2281. This screen identified the deubiquitylating enzyme USP11 as a participant in HR repair of DNA double-strand breaks. Silencing USP11 with siRNA leads to spontaneous DDR activation in otherwise undamaged cells and hypersensitivity to PARP inhibition, ionizing radiation, and other genotoxic stress agents. Moreover, we demonstrate that HR repair is defective in USP11-silenced cells. Finally, the recruitment of a subset of double-strand break repair proteins including RAD51 and 53BP1 to repair foci is misregulated in the absence of USP11 catalytic activity. Thus, our synthetic lethal approach identified USP11 as a component of the HR double-strand break repair pathway.
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23 MeSH Terms