ArticleJournal of experimental & clinical cancer research : CR2020
Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids.
Article in Journal of experimental & clinical cancer research : CR, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 108 citations in OpenAlex.
- Review
- Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.Molecular cancer · 2026Review
- Targeted Therapy and Immunotherapies in Hepatocellular Carcinoma: Mechanisms and Clinical Studies.MedComm · 2026Review
- YBX1 Promotes Drug Resistance in Hepatocellular Carcinoma and Serves as a Potential Therapeutic Target.Research square · 2026Article
- Identification of Bruceine A as a novel HSP90AB1 inhibitor for suppressing hepatocellular carcinoma growth.Journal of advanced research · 2026Article
- Targeting SPP1-CD44-Hedgehog Axis Elicits Therapeutic Effects in Hepatocellular Carcinoma by Suppressing Intratumoral Fibrosis.Cancer science · 2026Article
- Patient-Derived Models of Liver Cancer to Inform Clinical Treatment Paradigms: Recent Updates.Seminars in liver disease · 2026Review
- Ashwagandha (Withania somnifera) targets liver cancer stem cells via inhibiting Hedgehog signaling pathway in hepatocellular carcinoma.Medical oncology (Northwood, London, England) · 2026Article
- Human Liver Organoids as an Experimental Tool to Investigate Lipocalin-2 in Hepatic Inflammation.Cells · 2026Article
- Combining sorafenib with spermine and sphingosine synergistically enhances anticancer efficacy by modulating metabolic pathways and gut microbiome in hepatocellular carcinoma.International journal of biological sciences · 2026Article
- DNA-mediated ZNF649 downregulation modulates the Hedgehog signaling pathway to reduce the sensitivity of gastric cardia cancer to 5-FU.Journal of clinical biochemistry and nutrition · 2026Article
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- Combined downregulation of TGF-β1 and GRP78 is responsible for overcoming acquired sorafenib resistance, which is initiated by rewiring the cell surface CD44-GRP78-IGF-1R signaling circuit.Cancer gene therapy · 2025Article
- Decoding the role of cancer stem cells in digestive tract tumors: Mechanisms and therapeutic implications (Review).International journal of oncology · 2025Review
- Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance.Journal of hematology & oncology · 2025Review
- FBXO32 ubiquitination of SUFU promotes progression and lenvatinib resistance in hepatocellular carcinoma via hedgehog signaling.Medical oncology (Northwood, London, England) · 2025Article
- State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- Hepatocellular carcinoma: signaling pathways and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Modelling hepatocellular carcinoma microenvironment phenotype to evaluate drug efficacy.Scientific reports · 2025Article
- Modeling methods of different tumor organoids and their application in tumor drug resistance research.Cancer drug resistance (Alhambra, Calif.) · 2025Review
7 more citing papers are in PubMed but not listed here.
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9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived organoid (PDO) models to improve treatment efficacy.
methodsWe collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships.
resultsWe demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61.
conclusionsGANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.
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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.