PKC inhibition overcomes chemo-resistance in TNBC by restoring Aurora kinase B expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE250221 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:PKC inhibition overcomes chemo-resistance in TNBC by restoring Aurora kinase B expression
| PRJNA1052692 | ENA
Project description:Triple-negative breast cancer (TNBC) poses a significant challenge due to its high mortality rates, primarily attributed to resistance against chemotherapy regimens containing taxanes like paclitaxel. Thus, developing combinatorial strategies to override resistance is a pressing need. By taking advantage of a library screening with various kinase inhibitors, we found that the small-molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Mechanistically, dual treatment with paclitaxel and enzastaurin resulted in efficient mitotic arrest and subsequent cell death by restoring AURKB expression. Further analysis revealed that the GCN2-p-eIF2α axis was responsible for the posttranscriptional accumulation of AURKB upon combinatorial treatment. Finally, we confirmed that combinatorial regimens synergistically suppressed tumour growth in vivo in mouse models. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic.
| S-EPMC11915661 | biostudies-literature
Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells. RNA isolated from three independent passages of sensitive, Docetaxel and Paclitaxel resistant cell lines and purified using the Qiagen RNeasy Mini Kit. Total RNA was processed and hybridized to Affymetrix Genechip HU133A arrays.
2011-04-22 | E-GEOD-28784 | biostudies-arrayexpress
Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells.
2011-04-22 | GSE28784 | GEO
Project description:For patients with triple negative breast tumours (TNBCs), lacking receptors for oestrogen, progesterone or HER2 on their cell surface, chemotherapy is the main treatment. The taxanes, paclitaxel (PTX) and docetaxel, have become the most commonly-used chemotherapies for these kinds of breast cancer. Although several targeted therapies are currently undergoing clinical trials for TNBC, because of the heterogeneous nature of TNBCs, it is predicted that these may often be used in combination with chemotherapy. Therefore an understanding of the mechanisms of chemotherapy resistance will continue to be important for the treatment of these patients.
2015-09-02 | GSE60964 | GEO
Project description:The combination of immune checkpoint blockade (ICB) and chemotherapy holds promise for treating triple-negative breast cancer (TNBC), yet the underlying mechanisms remain incompletely understood. Here, we integrated previously published and newly generated single-cell RNA sequencing (scRNA-seq) data to investigate the tumor immune microenvironment (TIME) in advanced TNBC patients receiving various therapies, including paclitaxel, nab-paclitaxel, and their combinations with an anti-PD-L1 antibody atezolizumab. Notably, compared to atezolizumab plus paclitaxel, atezolizumab plus nab-paclitaxel primarily rewired TCF7+ stem-like effector memory CD8 T cells (Tsem) and CD4 follicular helper T (Tfh) cells. Nab-paclitaxel, but not paclitaxel, predominantly modulated the myeloid compartment, expanding mast cells and pro-inflammatory macrophage subsets. Our analyses in human TNBC and murine models highlighted the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by recruiting and activating T cells and B cells. In vivo experiments demonstrated that activating mast cells alongside PD-L1 blockade significantly attenuated tumor progression, suggesting mast cells as a promising adjunct for enhancing ICB therapy efficacy.
2025-02-12 | GSE266919 | GEO
Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
2017-01-26 | GSE86839 | GEO
Project description:Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.
2024-03-23 | GSE245935 | GEO
Project description:Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), whereas is effective in a portion of patients. Our clinical studies found that lipid homeostasis imbalance and dendritic cells (DCs) dysfunction contributed to the immunosuppressive microenvironment in the lymph nodes (LNs) of TNBC patients following immunotherapy, which greatly affected the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator, EMV@SS-Toy, involving a polysulfide bond-bridged mesoporous silica nanoparticles (SS-MSN) as a reactive oxygen species (ROS) scavenger and responsive carrier nucleus, loading with the (IRE1α-XBP1) inhibitor toyocamycin (Toy) and coating with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing via homologous targeting and chemokine-guided navigation, enabling a pathological ROS-responsive drug release, dual-stress pathway regulation, thereby restoring and DCs’ function and LNs’ immune microenvironment. As expected, the immunomodulator markedly boosted the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases and establishing long-term immune surveillance. Our study provides potent directions for translational immunotherapy through optimizing the LNs’ microenvironment in TNBC.
2024-10-01 | GSE270025 | GEO
Project description:For patients with triple negative breast tumours (TNBCs), lacking receptors for oestrogen, progesterone or HER2 on their cell surface, chemotherapy is the main treatment. The taxanes, paclitaxel (PTX) and docetaxel, have become the most commonly-used chemotherapies for these kinds of breast cancer. Although several targeted therapies are currently undergoing clinical trials for TNBC, because of the heterogeneous nature of TNBCs, it is predicted that these may often be used in combination with chemotherapy. Therefore an understanding of the mechanisms of chemotherapy resistance will continue to be important for the treatment of these patients. Given the pleiotropic nature of YB-1, the aim of this study was to understand whether there were mechanisms in addition to those discussed above, by which YB-1 controls response to PTX in TNBCs. We initially followed up two previously studied mechanisms, mediated by ABCB1/MDR1 and DUSP4. We then proceeded to use genomics to identify novel mechanisms by which YB-1 regulates the response of TNBCs to PTX. This analysis identified and experimentally validated EGR1, encoding the early growth response protein 1 (EGR1) as a previously undiscovered mechanism of YB-1-driven PTX resistance.
2015-09-02 | E-GEOD-60964 | biostudies-arrayexpress