ArticleBMC cancer2019
Overcoming acquired resistance to HSP90 inhibition by targeting JAK-STAT signalling in triple-negative breast cancer.
Article in BMC cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer.Investigational new drugs · 2020Trial
- Evolution of Hsp90 targeting: From stress biology to clinical translation.Cell stress & chaperones · 2026Review
- Flavonoid-modulated JAK-STAT signaling mitigates malignant transformation and drug resistance in breast tumors: A clinically relevant 3PM-guided innovation.Journal of advanced research · 2026Review
- Exploring Bakuchiol as an HSP90-Targeting Lead Against Triple-Negative Breast Cancer: Evidence from In Silico, In Vitro, and Synergy Studies.Journal of computer-aided molecular design · 2026Article
- Targeting signaling pathways in lymphoma: From molecular mechanisms to clinical breakthroughs.Chinese medical journal · 2026Review
- HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.Scientific reports · 2024Article
- Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies.Molecules (Basel, Switzerland) · 2023Article
- Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer.Cancer research and treatment · 2022Article
- Review
- Chaperonin containing TCP-1 (CCT/TRiC) is a novel therapeutic and diagnostic target for neuroblastoma.Frontiers in oncology · 2022Article
- Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities.Frontiers in molecular biosciences · 2022Review
- A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects.Theranostics · 2022Article
- JAK2 regulates paclitaxel resistance in triple negative breast cancers.Journal of molecular medicine (Berlin, Germany) · 2021Article
- Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Combination of Fish Oil and Selenium Enhances Anticancer Efficacy and Targets Multiple Signaling Pathways in Anti-VEGF Agent Treated-TNBC Tumor-Bearing Mice.Marine drugs · 2021Article
- Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer.Cancers · 2021Review
- The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer.Cell death & disease · 2021Article
- STAT3 and p53: Dual Target for Cancer Therapy.Biomedicines · 2020Review
- Important players in carcinogenesis as potential targets in cancer therapy: an update.Oncotarget · 2020Review
- Heat shock protein 90α in thymic epithelial tumors and non-thymomatous myasthenia gravis.Oncoimmunology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundDue to the lack of effective therapies and poor prognosis in TNBC (triple-negative breast cancer) patients, there is a strong need to develop effective novel targeted therapies for this subtype of breast cancer. Inhibition of heat shock protein 90 (HSP90), a conserved molecular chaperone that is involved in the regulation of oncogenic client proteins, has shown to be a promising therapeutic approach for TNBC. However, both intrinsic and acquired resistance to HSP90 inhibitors (HSP90i) limits their effectiveness in cancer patients.
methodsWe developed models of acquired resistance to HSP90i by prolonged exposure of TNBC cells to HSP90i (ganetespib) in vitro. Whole transcriptome profiling and a 328-compound bioactive small molecule screen were performed on these cells to identify the molecular basis of acquired resistance to HSP90i and potential therapeutic approaches to overcome resistance.
resultsAmong a panel of seven TNBC cell lines, the most sensitive cell line (Hs578T) to HSP90i was selected as an in vitro model to investigate acquired resistance to HSP90i. Two independent HSP90i-resistant clones were successfully isolated which both showed absence of client proteins degradation, apoptosis induction and G2/M cell cycle arrest after treatment with HSP90i. Gene expression profiling and pathway enrichment analysis demonstrate significant activation of the survival JAK-STAT signalling pathway in both HSP90i-resistant clones, possibly through IL6 autocrine signalling. A bioactive small molecule screen also demonstrated that the HSP90i-resistant clones showed selective sensitivity to JAK2 inhibition. Inhibition of JAK and HSP90 caused higher induction of apoptosis, despite prior acquired resistance to HSP90i.
conclusionsAcquired resistance to HSP90i in TNBC cells is associated with an upregulated JAK-STAT signalling pathway. A combined inhibition of the JAK-STAT signalling pathway and HSP90 could overcome this resistance. The benefits of the combined therapy could be explored further for the development of effective targeted therapy in TNBC patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.