ArticleCancer research2015
Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma.
Article in Cancer research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 107 citations in OpenAlex.
- Pharmacogenomic insights: IL-23R and ATG-10 polymorphisms in Sorafenib response for hepatocellular carcinoma.Clinical and experimental medicine · 2025Trial
- Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide.Clinical and translational science · 2017Trial
- Stemness plasticity in hepatocellular carcinoma: spatial niches and therapeutic implications.Journal of liver cancer · 2026Article
- Article
- Cathepsin Inhibitor Suppresses the Growth of Ectopic Hepatocellular Carcinoma Tumors in Mouse Models.ACS pharmacology & translational science · 2026Article
- Targeting PIP5K ameliorates hepatic cancer by inhibiting PI3K/AKT and the autophagy mechanism and enhancing ROS-mediated apoptosis.Frontiers in pharmacology · 2026Article
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- Emerging role of exosomes in cancer therapy: progress and challenges.Molecular cancer · 2025Review
- Review
- A novel single-cell model reveals ferroptosis-associated biomarkers for individualized therapy and prognostic prediction in hepatocellular carcinoma.BMC biology · 2024Article
- Coordinated activation of DNMT3a and TET2 in cancer stem cell-like cells initiates and sustains drug resistance in hepatocellular carcinoma.Cancer cell international · 2024Article
- Article
- Mechanisms of Sorafenib Resistance in HCC Culture Relate to the Impaired Membrane Expression of Organic Cation Transporter 1 (OCT1).Journal of hepatocellular carcinoma · 2024Article
- Lenvatinib Induces Immunogenic Cell Death and Triggers Toll-Like Receptor-3/4 Ligands in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2023Article
- Based on disulfidptosis-related glycolytic genes to construct a signature for predicting prognosis and immune infiltration analysis of hepatocellular carcinoma.Frontiers in immunology · 2023Article
- Article
- WD repeat domain 48 promotes hepatocellular carcinoma progression by stabilizing c-Myc.Journal of cellular and molecular medicine · 2022Article
- Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Review
- Differential in vitro effects of targeted therapeutics in primary human liver cancer: importance for combined liver cancer.BMC cancer · 2022Article
- Perindopril sensitizes hepatocellular carcinoma to chemotherapy: A possible role of leptin / Wnt/ β-catenin axis with subsequent inhibition of liver cancer stem cells.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Acquired evasive resistance is a major limitation of hepatocellular carcinoma (HCC) treatment with the tyrosine kinase inhibitor (TKI) sorafenib. Recent findings suggest that resistance to sorafenib may have a reversible phenotype. In addition, loss of responsiveness has been proposed to be due to a gradual decrease in sorafenib plasma levels in patients. Here, the possible mechanisms underlying reversible sorafenib resistance were investigated using a Hep3B-hCG orthotopic human xenograft model of locally advanced HCC. Tissue and plasma sorafenib and metabolite levels, downstream antitumor targets, and toxicity were assessed during standard and dose-escalated sorafenib treatment. Drug levels were found to decline significantly over time in mice treated with 30 mg/kg sorafenib, coinciding with the onset of resistance but a greater magnitude of change was observed in tissues compared with plasma. Skin rash also correlated with drug levels and tended to decrease in severity over time. Drug level changes appeared to be partially tumor dependent involving induction of tumoral CYP3A4 metabolism, with host pretreatment alone unable to generate resistance. Escalation from 30 to 60 mg/kg sorafenib improved antitumor efficacy but worsened survival due to excessive body weight loss. Microvessel density was inhibited by sorafenib treatment but remained suppressed over time and dose increase. In conclusion, tumor CYP3A4 induction by sorafenib is a novel mechanism to account for variability in systemic drug levels; however, declining systemic sorafenib levels may only be a minor resistance mechanism. Escalating the dose may be an effective treatment strategy, provided toxicity can be controlled.
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Registered trials
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.