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 |
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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.
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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. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment
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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)
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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. RNA-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment over time
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