scholarly journals ONC201 and an MEK Inhibitor Trametinib Synergistically Inhibit the Growth of Triple-Negative Breast Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1410
Author(s):  
Bora Lim ◽  
Christine B. Peterson ◽  
Alexander Davis ◽  
Elin Cho ◽  
Troy Pearson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Protein Expression ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Mek Inhibitor ◽  
Expression Levels

Triple-negative breast cancer (TNBC) is a heterogeneous group of estrogen, progesterone, and HER2-negative breast cancers with poor clinical outcomes. The imipridone ONC201 is a G-protein-coupled dopamine receptor D2 modulator and an allosteric agonist of the mitochondrial protease caseinolytic protease P(ClpP), which induces apoptosis. Here, we aimed to develop a novel ONC201-based combination therapy targeting TNBC. We performed a reverse-phase protein array analysis of ONC201-treated/-untreated and -sensitive/-resistant cell lines to identify potential predictive biomarkers. A principal component analysis using measured protein expression levels, the apoptosis score (AS), and heatmaps of all the measured protein and AS-related protein expression levels did not show a clear correlation between the expression levels of a specific protein and ONC201 efficacy. Three-dimensional RNA interference kinome-wide library screening revealed the MAPK and PI3K/Akt pathways as potential synergistic therapeutic partners. The combination with the MEK inhibitor trametinib successfully inhibited the growth of both ONC201-sensitive/-resistant TNBC cell lines. The baseline ClpP level correlated with the efficacy of single-agent ONC201. Single and combination therapy increased caspase 3/7 activity. The predictive biomarkers and a detailed mechanism of synergy beyond an induction of caspase activation should be tested for translation into future studies.

Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer.

2020 ◽  
Author(s):  
Todd Pitts ◽  
Dennis M Simmons ◽  
Stacey M Bagby ◽  
Sarah J Hartman ◽  
Betelehem W Yacob ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Single Agent ◽  
Cell Analysis ◽  
Preclinical Models ◽  
Pdx Models ◽  
Live Cell Analysis

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype defined by lack of hormone receptor expression and non-amplified HER2. Adavosertib (AZD1775) is a potent, small molecule, ATP-competitive inhibitor of the Wee1 kinase that potentiates the activity of many DNA-damaging chemotherapeutics and is currently in clinical development for multiple indications. The purpose of this study was to investigate the combination of AZD1775 and capecitabine/5-FU in preclinical TNBC models. Methods: TNBC cell lines were treated with AZD1775 and 5-FU and cellular proliferation was assessed in real-time using IncuCyte® Live Cell Analysis. Apoptosis was assessed via the Caspase-Glo 3/7 assay system. Western blotting was used to assess changes in expression of downstream effectors. TNBC PDX models were treated with AZD1775, capecitabine, or the combination and assessed for tumor growth inhibition. Results: From the initial PDX screen, two of the four TNBC PDX models demonstrated a better response in the combination treatment than either of the single agents. As confirmation, two PDX models were expanded for statistical comparison . Both PDX models demonstrated a significant growth inhibition in the combination versus either of the single agents. (TNBC012, p<0.05 combo vs adavosertib or capecitabine, TNBC013, p<0.01 combo vs adavosertib or capecitabine ). An enhanced antiproliferative effect was observed in the adavosertib/5-FU combination treatment as measured by live cell analysis. An increase in apoptosis was observed in two of the four cell lines in the combination when compared to single agent treatment. Treatment with single agent adavosertib resulted in an increase in p-CDC2 in a dose dependent manner that was also observed in the combination treatment. Similar results were observed with γH2AX in two of the four cell lines tested. No significant changes were observed in Bcl-xL following treatment in any of the cell lines. Conclusions: The combination of adavosertib and capecitabine/5-FU demonstrated enhanced combination effects both in vitro and in vivo in preclinical models of TNBC. These results support the clinical investigation of this combination in patients with TNBC, including those with brain metastasis given the CNS penetration of both agents.

scholarly journals High ERK Protein Expression Levels Correlate with Shorter Survival in Triple‐Negative Breast Cancer Patients

2012 ◽  
Vol 17 (6) ◽  
pp. 766-774 ◽  
Author(s):  
Chandra Bartholomeusz ◽  
Ana M. Gonzalez‐Angulo ◽  
Ping Liu ◽  
Naoki Hayashi ◽  
Ana Lluch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Expression Levels

Abstract 3140: High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer

2010 ◽  
Author(s):  
Chandra Bartholomeusz ◽  
Ana Gonzalez-Angulo ◽  
Ping Liu ◽  
Naoki Hayashi ◽  
Gabriel N. Hortobagyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Levels

scholarly journals An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vera E. van der Noord ◽  
Ronan P. McLaughlin ◽  
Marcel Smid ◽  
John A. Foekens ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Mek Inhibitor ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Tnbc Cell

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical prognosis and limited targeted treatment strategies. Kinase inhibitor screening of a panel of 20 TNBC cell lines uncovered three critical TNBC subgroups: 1) sensitive to only MEK inhibitors; 2) sensitive to only Akt inhibitors; 3) resistant to both MEK/Akt inhibitors. Using genomic, transcriptomic and proteomic datasets of these TNBC cell lines we unravelled molecular features associated with the MEK and Akt drug resistance. MEK inhibitor-resistant TNBC cell lines were discriminated from Akt inhibitor-resistant lines by the presence of PIK3CA/PIK3R1/PTEN mutations, high p-Akt and low p-MEK levels, yet these features could not distinguish double-resistant cells. Gene set enrichment analyses of transcriptomic and proteomic data of the MEK and Akt inhibitor response groups revealed a set of cell cycle-related genes associated with the double-resistant phenotype; these genes were overexpressed in a subset of breast cancer patients. CDK inhibitors targeting the cell cycle programme could overcome the Akt and MEK inhibitor double-resistance. In conclusion, we uncovered molecular features and alternative treatment strategies for TNBC that are double-resistant to Akt and MEK inhibitors.

scholarly journals Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Qiongyu Hao ◽  
Piwen Wang ◽  
Pranabananda Dutta ◽  
Seyung Chung ◽  
Qun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Triple Negative Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Triple Negative ◽  
Single Agent ◽  
Antitumor Efficacy ◽  
Secondary Resistance ◽  
Mtor Protein

AbstractThe abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.

scholarly journals How I treat metastatic triple-negative breast cancer

ESMO Open ◽  
2019 ◽  
Vol 4 (Suppl 2) ◽  
pp. e000504 ◽  
Author(s):  
Rafael Caparica ◽  
Matteo Lambertini ◽  
Evandro de Azambuja
Keyword(s):  
Breast Cancer ◽  
Disease Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Treatment Algorithm ◽  
Predictive Biomarkers ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Triple-negative breast cancer (TNBC) is associated with a high risk of recurrence and generally a bad prognosis. More than one-third of patients with TNBC will present distant metastases during the course of their disease. Although chemotherapy has been the main treatment option for metastatic TNBC for a long time, this scenario has changed recently with the advent of the polyadenosine diphosphate-ribose polymerase inhibitors (PARPis) for patients harbouring a mutation in the BRCA genes (BRCAmut) and also with the results of immunotherapy in patients with PD-L1-positive tumours. The present manuscript proposes a treatment algorithm for patients with metastatic TNBC based on the currently available, most relevant literature on the topic. For patients with a BRCAmut and able to tolerate chemotherapy, we recommend initiating treatment with platins (carboplatin/cisplatin) and to start PARPis at disease progression. For patients with PD-L1-positive tumours (PD-L1 expression on tumour-infiltrating immune cells ≥1%), we recommend first-line treatment with nab-paclitaxel and atezolizumab, when available. In patients without a BRCA mutation and with PD-L1-negative tumours, we recommend single-agent chemotherapy with taxanes (paclitaxel or docetaxel) as a first-line treatment. In patients with a high disease burden or who are very symptomatic, combinations such as anthracyclines plus cyclophosphamide or platins with taxanes are valid options. Chemotherapy should be maintained until the occurrence of disease progression or limiting toxicities. After progression to first-line chemotherapy, anthracyclines are an option for patients who received taxanes and vice versa. For patients who progressed to taxanes and anthracyclines, or who present contraindications to these agents, fluorouracil/capecitabine, eribulin, gemcitabine, cisplatin/carboplatin, vinorelbine and ixabepilone are alternatives. The treatment of TNBC is constantly evolving, and the inclusion of patients in ongoing trials evaluating new targeted agents, immunotherapy and predictive biomarkers should be encouraged, in an attempt to improve metastatic TNBC treatment outcomes.

scholarly journals HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and Microenvironmental Induced Resistance

2020 ◽  
Vol 10 ◽  
Author(s):  
Nicoleta Sinevici ◽  
Bahar Ataeinia ◽  
Veronica Zehnder ◽  
Kevin Lin ◽  
Lauren Grove ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Human Cancer ◽  
Single Agent ◽  
Mapk Signaling ◽  
Akt Pathway ◽  
Compensatory Mechanisms ◽  
Tnbc Cell

Triple Negative Breast Cancer (TNBC) is an aggressive form of Breast Cancer (BC). Numerous kinase inhibitors (KI) targeting different pathway nodes have shown limited benefit in the clinical setting. In this study, we aim to characterize the extent of HER3 reliance and to define the effect of Neuregulin (NRG) isoforms in TNBCs. Basal and Claudin type TNBC cell lines were treated with a range of small molecule inhibitors, in the presence or absence of the HER3 ligand NRG. Single agent and combination therapy was also evaluated in human cancer cell lines through viability and biochemical assessment of the AKT/MAPK signaling pathway. We show that Basal (BT20, HCC-70, and MDA-MB-468) and Claudin type (MDA-MB-231, BT-549) TNBC cell lines displayed differential reliance on the HER family of receptors. Expression and dynamic HER3 upregulation was predominant in the Basal TNBC subtype. Furthermore, the presence of the natural ligand NRG showed potent signaling through the HER3-AKT pathway, significantly diminishing the efficacy of the AKT and PI3K inhibitors tested. We report that NRG augments the HER3 feedback mechanism for continued cell survival in TNBC. We demonstrate that combination strategies to effectively block the EGFR-HER3-AKT pathway are necessary to overcome compensatory mechanisms to NRG dependent and independent resistance mechanisms. Our findings suggests that the EGFR-HER3 heterodimer forms a major signaling hub and is a key player in tumorigenesis in Basal but not Claudin type TNBC tested. Thus, HER3 could potentially serve as a biomarker for identifying patients in which targeted therapy against the EGFR-HER3-AKT axis would be most valuable.

scholarly journals Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiuzhi Zhu ◽  
Li Chen ◽  
Binhao Huang ◽  
Xiaoguang Li ◽  
Liu Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Wnt Signalling ◽  
Tnbc Cell

Abstract Background PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib. Methods We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically. Results We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib. Conclusions Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.

scholarly journals A Network Approach to Identify Biomarkers of Differential Chemotherapy Response Using Patient-Derived Xenografts of Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Varduhi Petrosyan ◽  
Lacey E. Dobrolecki ◽  
Lillian Thistlethwaite ◽  
Alaina N Lewis ◽  
Christina Sallas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Clinical Samples ◽  
Chemotherapy Response ◽  
Expression Platform ◽  
Preclinical Trials

Triple negative breast cancer (TNBC) is a highly heterogeneous set of diseases that has, until recently, lacked any FDA-approved, molecularly targeted therapeutics. Thus, systemic chemotherapy regimens remain the standard of care for many. Unfortunately, even combination chemotherapy is ineffective for many TNBC patients, and side-effects can be severe or lethal. Identification of predictive biomarkers for chemotherapy response would allow for the prospective selection of responsive patients, thereby maximizing efficacy and minimizing unwanted toxicities. Here, we leverage a cohort of TNBC PDX models with responses to single-agent docetaxel or carboplatin to identify biomarkers predictive for differential response to these two drugs. To demonstrate their ability to function as a preclinical cohort, PDX were molecularly characterized using whole-exome DNA sequencing, RNAseq transcriptomics, and mass spectrometry-based total proteomics to show proteogenomic consistency with TCGA and CPTAC clinical samples. Focusing first on the transcriptome, we describe a network-based computational approach to identify candidate epithelial and stromal biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (ITGA7, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). Biomarker panels are predictive in PDX expression datasets (RNAseq and Affymetrix) for both taxane (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating both cross expression platform and cross drug class robustness. Biomarker panels were also predictive in clinical datasets with response to cisplatin or paclitaxel, thus demonstrating translational potential of PDX-based preclinical trials. This network-based approach is highly adaptable and can be used to evaluate biomarkers of response to other agents.

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer

2020 ◽  
Vol 20 (8) ◽  
pp. 586-602
Author(s):  
Manzoor A. Mir ◽  
Hina Qayoom ◽  
Umar Mehraj ◽  
Safura Nisar ◽  
Basharat Bhat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Acquired Resistance ◽  
Pi3k Pathway ◽  
Chemotherapeutic Agents ◽  
High Grade ◽  
Efficient Treatment

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.

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