Drug Repurposing Identifies Proteasome Inhibitors as Antiproliferative Agents Counteracting Inflammation-Driven Chemoresistance in Triple-Negative Breast Cancer Organoids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Assoc. Prof. Rossukon Kaewkhaw
PROVIDER: PXD059504 | JPOST Repository | Tue Jan 06 00:00:00 GMT 2026
REPOSITORIES: jPOST
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| BC-05%20BTZ_1.mzXML | Mzxml | |||
| BC-05%20BTZ_2.mzXML | Mzxml | |||
| BC-05%20BTZ_3.mzXML | Mzxml | |||
| BC-05%20CFZ_1.mzXML | Mzxml | |||
| BC-05%20CFZ_2.mzXML | Mzxml |
Items per page: 5 1 - 5 of 20 |
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Project description:Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options, characterized by high relapse rates and poor survival outcomes due to chemoresistance. This study aimed to repurpose FDA-approved drugs for TNBC and investigate their mechanisms of action in inhibiting cancer cells and counteracting chemoresistance. Methods: Patient-derived TNBC organoids were generated from residual tumors of patients with disease progression despite receiving standard-of-care chemotherapy. A high throughput screen of 133 FDA-approved anticancer drugs was performed on the organoids to identify potent cytotoxic agents using image-based analysis and drug-sensitivity assays. Drug response dynamics were analyzed to evaluate the efficacy of these agents in counteracting clinical drug resistance. The molecular and functional effects of the identified agents were investigated through proteomic and transcriptomic analyses, as well as translation and cell cycle assays. Results: Proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) were identified as potent candidates for inhibiting TNBC organoids. These drugs significantly downregulated ribosomal protein expression, suppressing translation and disrupting cell cycle progression. While TNBC organoids exhibited resistance to conventional chemotherapeutics, they were susceptible to proteasome inhibitors. Transcriptomic profiling revealed that proteasome inhibitors counteracted inflammation-driven resistance to doxorubicin (DXR) by exerting dual anti-inflammatory and anti-proliferative effects. Conclusions: This study identifies proteasome inhibition as a promising therapeutic strategy for TNBC, offering a novel approach to address unmet clinical needs. Using patient-derived organoids, this work highlights inflammation as a driver of DXR resistance and establishes it as a therapeutic target effectively counteracted by proteasome inhibitors.
2026-01-18 | GSE287429 | GEO
Project description:Triple negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain containing proteins affecting the expression of transcription factors (TFs), therefore modifying the expression of relevant oncogenic genes. We decided to performed gene-set enrichment analyses to get insights into the mechanism of action of these compounds. We treated cells with JQ1 and extracted RNA at 12 and 24 hours.
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Project description:Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channels increases in vitro invasion, tumor growth, and metastasis, inducing changes in gene expression associated with cell adhesion. We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new treatment strategy for metastatic TNBC by repurposing FDA-approved potassium channel blockers. Our results provide an understanding of a mechanism by which the bioelectricity regulates cancer cell invasion and metastasis that can advance the development of a potential new class of TNBC therapeutics.
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Project description:Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive, metastatic, and clinically challenging breast cancer subtype with worst prognosis. Despite survival dependency on the proteasome pathway genes, the FDA-approved proteasome inhibitors induced minimal clinical response in TNBC patients due to weaker proteasome inhibition. Here, we show that a novel proteasome inhibitor Marizomib (Mzb), inhibited multiple proteasome catalytic activities and induced better anti-tumor response in TNBC cell line and patient-derived xenografts alone and in combination with a standard-of-care chemotherapy, doxorubicin. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Development of metastatic disease, especially brain metastasis, remains a reason for a greater mortality rate amongst TNBC patients. Mzb reduces lung and brain metastasis in vivo by reducing circulating tumor cells and the expression of multiple epithelial-to-mesenchymal genes. We also demonstrate that Mzb-induced OXPHOS inhibition upregulates glycolysis to fulfill the metabolic demand of TNBC cells and hence, combined inhibition of glycolysis with Mzb leads to a synergistic anti-cancer activity in vivo. Collectively, our data provide a strong rationale for the clinical evaluation of Mzb in primary and metastatic TNBC patients.
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Project description:Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC.
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Project description:Triple-negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor α (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy, recently supplemented by immunotherapy [37296893]. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including gamma secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. We confirmed that SS, a known gamma secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, the anti-tumor effects of SS were significantly enhanced when combined with α-PD1 immunotherapy in our TNBC organoids and in vivo. Our data support further investigation of SS for the treatment of TNBC, in conjunction with standard of care chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option solution for a patient population in need of effective therapies.
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Project description:Triple negative breast cancer (TNBC) represents a challenging tumor type due to their poor prognosis and limited treatment options. It is well recognize that clinical and molecular heterogeneity of TNBC is driven in part by mRNA and lncRNAs. To stratify TNBCs, we profiled mRNAs and lncRNA in 158 adjuvant TNBC tumors using an Affymetrix microarray platform. Lehmann clustering analysis allowed us to identify TNBC subtypes featuring unique lncRNA expression patterns, disease free and overall survival rates and particular gene ontology enrichments (performed with GSEA algorithm).
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Project description:Triple negative breast cancer (TNBC) represents a challenging tumor type due to their poor prognosis and limited treatment options. It is well recognize that clinical and molecular heterogeneity of TNBC is driven in part by mRNA and lncRNAs. To stratify TNBCs, we profiled mRNAs and lncRNA in 158 adjuvant TNBC tumors using an Affymetrix microarray platform. Lehmann clustering analysis allowed us to identify TNBC subtypes featuring unique lncRNA expression patterns, disease free and overall survival rates and particular gene ontology enrichments (performed with GSEA algorithm).
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Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)
2016-01-07 | E-GEOD-63284 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment
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