ArticleOncotarget2018
Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 76 citations in OpenAlex.
- Mitochondrial-Based Nanomedicine in Treatment of Liver Cancer.Molecular biotechnology · 2026Review
- Can Cancer Cell Line In Vitro Radioembolization Model Help to Understand How Beta Radiation Affects Liver Tumor and Improve Treatment Results?International journal of molecular sciences · 2026Article
- Immune remodeling via mitochondria-dependent STING activation enhances cabozantinib response in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2026Article
- Probiotics Mixture, Prohep: a Potential Adjuvant for Low-Dose Sorafenib in Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma Suppression Through Modulating Gut Microbiota.Probiotics and antimicrobial proteins · 2026Article
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- Mitochondrially Targeted p53-Bad* Fusion Gene Therapy Promotes Apoptosis in Hepatocellular Carcinoma by Pan-Bcl-2 Inhibition.Molecular pharmaceutics · 2025Article
- Genome-wide CRISPR-Cas9 screens identify BCL family members as modulators of response to regorafenib in experimental glioma.Neuro-oncology · 2025Article
- Exploring the Molecular Mechanism of 1,25(OH)Current issues in molecular biology · 2025Article
- Small-molecule-based targeted therapy in liver cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.Nature cancer · 2024Article
- Article
- [Liver cancer treatment with mitochondrial homeostasis].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2024Article
- Prognostic signature and immune efficacy of mJournal of Cancer · 2024Article
- The Role of Bcl-2 Family Proteins and Sorafenib Resistance in Hepatocellular Carcinoma.International journal of cell biology · 2024Review
- A feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC.Cancer & metabolism · 2023Article
- Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis.British journal of cancer · 2023Article
- Thymoquinone, piperine, and sorafenib combinations attenuate liver and breast cancers progression: epigenetic and molecular docking approaches.BMC complementary medicine and therapies · 2023Article
- Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact.Cancers · 2022Review
- Analysis of the role of m6A and lncRNAs in prognosis and immunotherapy of hepatocellular carcinoma.Heliyon · 2022Article
- Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.Cell death & disease · 2022Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.
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