scholarly journals PRMT1 Confers Resistance to Olaparib via Modulating MYC Signaling in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 (10) ◽  
pp. 1009
Author(s):  
Wen-Jing Hsu ◽  
Cheng-Hsun Chen ◽  
Yu-Chu Chang ◽  
Chia-Hsiung Cheng ◽  
Ying-Huei TsaI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Protein Stability ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Bioinformatic Analysis ◽  
Parp Inhibitors ◽  
Methyl Transferase

Treatment of triple-negative breast cancer (TNBC) remains an unmet clinical need owing to its lack of an efficient therapeutic target. The targeting of DNA repair by poly(ADP-ribose) polymerase (PARP) inhibitors has shown benefit for patients with the BRCA variation. However, sensitivities to the PARP inhibitors were reported regardless of BRCA status. Thus, exploring the underlying mechanisms is imperative. Herein, we identified that breast cancer cells with an elevated expression of protein arginine methyl transferase 1 (PRMT1) was associated with therapeutic sensitivity to the PARP inhibitor olaparib. The results of cell viability and colony formation assays indicated that the suppression of PRMT1 by small hairpin RNA or by the chemical inhibitor increased sensitivity to olaparib in human TNBC MDA-MB-231 and BT549 cells. Bioinformatic analysis revealed that PRMT1 expression was significantly associated with the MYC signature, and TNBC cells with higher PRMT1 and the MYC signature were associated with therapeutic sensitivity to olaparib. Mechanistic studies further demonstrated that knockdown of PRMT1 reduced the c-Myc protein level and downregulated the expression of MYC downstream targets, whereas overexpression of PRMT1 enhanced c-Myc protein expression. Moreover, the overexpression of PRMT1 promoted c-Myc protein stability, and the inhibition of PRMT1 downregulated c-Myc protein stability. Accordingly, the knockdown of PRMT1 inhibited homologous recombination gene expression. These data indicate that PRMT1 is instrumental in regulating DNA repair, at least in part, by modulating c-Myc signaling. Our data highlighted the PRMT1/c-Myc network as a potential therapeutic target in patients with TNBC.

scholarly journals PARP Inhibitor Olaparib Use in a BRCA1-Positive Patient With Metastatic Triple-Negative Breast Cancer, Without the Initial Use of Platinum-Based Chemotherapy, Showing Significant Rapid Near Resolution of Large Liver Metastasis While Patient Experienced Gout-Like Symptoms

2019 ◽  
Vol 7 ◽  
pp. 232470961986498 ◽  
Author(s):  
Trevanne Matthews Hew ◽  
Lara Zuberi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Management Options ◽  
Federal Drug Administration ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers diagnosed worldwide. This subtype of breast cancer tends to behave more aggressively, and unlike other breast cancer subtypes, there are no standard targeted treatments for most patients. However, up to 20% of patients with TNBC harbor a breast cancer gene (BRCA) mutation, particularly in BRCA1. For patients who carry this gene mutation, this opens the door for new management options by the use of newer agents such as polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the metastatic setting. Given that this is uncommon and that PARP inhibitors have only recently received Federal Drug Administration approval, the experience with these drugs is relatively new. In this article, we present a case of a patient treated in this setting with olaparib who developed an unanticipated side effect as a result of the high efficacy of the drug.

Effect of metformin on PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 expression in triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1063-1063 ◽  
Author(s):  
Ye Han ◽  
Chia-Wei Li
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Mesenchymal Transition

1063 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors have been described in some patients lowering overall response rates. The mechanisms underlying PARP inhibitor (PARPi) resistance are an area of active investigation. Methods: PARPi adaptive resistant clones (MDA-MB-468, MDA-MB-231, HCC1806) were generated in triple-negative breast cancer cell lines. Through morphologic observation and functional analysis, we evaluated epithelial-mesenchymal transition (EMT) and changes in immune checkpoint programmed death-ligand 1 (PD-L1). We also downregulated the expression of PD-L1 by shRNA to study the role of PD-L1 in PARPi resistance. We evaluated the immunology sensitivity to cytotoxic T cell upon PD-L1 change using a murine ex-vivo CD8+ T cell killing assay and a comparison of total killing cells percentage per well. Results: We demonstrated that inhibition of PARP enhances EMT, which induces phosphorylation of Akt at S473. This in turn upregulates the expression of PD-L1 by 2-3 fold in triple-negative breast cancer cells. In addition, PARPi–induced EMT occurred independent of PD-L1 upregulation in triple-negative breast cancer cells. Metformin administration (10µM) was found to reverse EMT by blocking the p-Akt S473 axis through activation of AMPK, resulting in downregulation of PD-L1 expression and sensitizing PARPi-resistant cancer cells to T cell killing. Conclusions: In summary, we identified that induction of EMT is a new mechanism for PARP inhibitor resistance. Metformin was able to reverse EMT and therefore a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to T cells.

scholarly journals PARP inhibitor increases chemosensitivity by upregulating miR-664b-5p in BRCA1-mutated triple-negative breast cancer

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Wei Song ◽  
Lin Tang ◽  
Yumei Xu ◽  
Jing Xu ◽  
Wenwen Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Migration And Invasion ◽  
Therapy Regimen ◽  
Xenograft Models ◽  
Underlying Mechanisms

Abstract Emerging evidence has shown that adding poly(ADP-ribose) polymerase (PARP) inhibitors to chemotherapy regimens is superior to the control regimens alone in BRCA1-mutated triple-negative breast cancer (TNBC) patients, but their underlying mechanisms have not been fully elucidated. In this study, using miRNA microarray analysis of two BRCA1-mutated TNBC cell lines, we found that miR-664b-5p expression was increased after adding a PARP inhibitor, olaparib, to a carboplatin (CBP) plus gemcitabine (GEM) therapy regimen. Functional assays showed miR-664b-5p overexpression inhibited proliferation, migration and invasion in BRCA1-mutated TNBC cells. CCNE2 was identified as a novel functional target of miR-664b-5p, and CCNE2 knockdown revealed effects similar to those observed with miR-664b-5p overexpression. Both CCNE2 knockdown and miR-664b-5p overexpression significantly increased the chemosensitivity of BRCA1-mutated TNBC cells. In addition, in vivo studies indicated that miR-664b-5p inhibited tumour growth compared with the control in tumour xenograft models, and we also found that CCNE2 expression was inversely correlated with miR-664b-5p expression in 90 TNBC patient samples. In conclusion, miR-664b-5p functions as a tumour suppressor and has an important role in the regulation of PARP inhibitors to increase chemosensitivity by targeting CCNE2. This may be one of the possible mechanisms by which PARP inhibitors increase chemosensitivity in BRCA1-mutated TNBC.

scholarly journals Combining PD-1/PD-L1 inhibitor and PARP inhibitor: a new perspective on the treatment of triple negative breast cancer

2021 ◽  
Vol 5 (2.1) ◽  
pp. 24
Author(s):  
Ruilian Xie
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Research Progress ◽  
Survival Prognosis ◽  
Combined Use ◽  
New Perspective

Compared with other types of breast cancer, triple negative breast cancer has a poor survival prognosis due to its high aggressiveness and lack of effective therapeutic targets. Immune checkpoint (PD-1/PD-L1 and CTL-4) inhibitors have emerged as a breakthrough therapy in the treatment in various metastatic cancers. PARP inhibitors promote DNA damage in tumor cells, not only promoting immune initiation through a series of molecular mechanisms, but also leading to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. Therefore, the combination of the two inhibitors can improve the efficacy of tumor treatment. We reviewed the research progress of their combined use in triple negative breast cancer, and put forward relevant ideas for further development, hoping to find the best treatment mode of the combined use of the two.

scholarly journals Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 2056
Author(s):  
Kitti Andreidesz ◽  
Balazs Koszegi ◽  
Dominika Kovacs ◽  
Viola Bagone Vantus ◽  
Ferenc Gallyas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Combined Treatment ◽  
Parp Inhibition ◽  
Akt Pathway ◽  
Platinum Compound ◽  
Mcf7 Cells ◽  
Cancer Line

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.

scholarly journals An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Erica M. Stringer-Reasor ◽  
Jori E. May ◽  
Eva Olariu ◽  
Valerie Caterinicchia ◽  
Yufeng Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Repair ◽  
Pilot Study ◽  
Expression Analysis ◽  
Triple Negative Breast Cancer ◽  
Gene Expression Analysis ◽  
Triple Negative ◽  
Egfr Inhibition ◽  
Link Type

Abstract Background Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Results Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Trial registration ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

scholarly journals Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor

2021 ◽  
Author(s):  
Dandan Song ◽  
Huan He ◽  
Indranil Sinha ◽  
Linnea Hases ◽  
Feifei Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor

Abstract 1066: Pre-clinical combination of a PARP inhibitor, talazoparib, and carboplatin in triple-negative breast cancer

2021 ◽  
Author(s):  
Alexia Cotte ◽  
Michèle Beniey ◽  
Takrima Haque ◽  
Nelly Béchir ◽  
Audrey Hubert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor
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