ArticleScientific reports2017
Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
What it found
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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
49 citing papers in PubMed, 81 citations in OpenAlex.
- Comparison of the Effects of Sorafenib and Stem Cell Secretome on HepG2 Cancer Cells with Respect to the Ras/Raf/MEK/ERK Pathway.Journal of clinical medicine · 2026Article
- Identification of Changes in the Transcriptome Profile of Human Hepatoma HepG2 Cells Exposed to Combined Sorafenib and Cannabis Treatment.International journal of molecular sciences · 2026Article
- LZTR1 Loss Reduces Vimentin Expression and Motility in Hep3B Hepatocellular Carcinoma Cells.International journal of molecular sciences · 2026Article
- Sorafenib nanomedicine in HCC: nano-bio interactions and combination therapies.Journal of nanobiotechnology · 2026Review
- Nanomaterial-based strategies to overcome sorafenib resistance in hepatocellular carcinoma: from mechanistic insights to translational applications.Frontiers in oncology · 2026Article
- CXCR4-Targeted Nanotherapeutics: A Promising Approach for Liver Fibrosis and Hepatocellular Carcinoma Management.International journal of nanomedicine · 2026Review
- Targeting the chemokine receptor CXCR4 for cancer therapies.Biomarker research · 2025Review
- Impact of COVID-19 infection on genitourinary cancer management. SOGUG-COVID-19: A spanish, multicenter, observational study.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Observational
- SERPING1 Reduces Cell Migration via ERK-MMP2-MMP-9 Cascade in Sorafenib- Resistant Hepatocellular Carcinoma.Environmental toxicology · 2025Article
- Co-Assembled Nanoparticles Comprising Sorafenib and Hederagenin Derivative for Enhanced Anti-Hepatic Fibrosis Activity.International journal of nanomedicine · 2025Article
- Molecular Targets and Nano-Technological Approaches in the Treatment of Hepatic Carcinoma.Current cancer drug targets · 2025Review
- IDO1 Inhibitor RY103 Suppresses Trp-GCN2-Mediated Angiogenesis and Counters Immunosuppression in Glioblastoma.Pharmaceutics · 2024Article
- Review
- Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications.International journal of molecular sciences · 2023Review
- The current status and future of PD-L1 in liver cancer.Frontiers in immunology · 2023Review
- Small-molecule High-throughput Screening Identifies an MEK Inhibitor PD198306 that Enhances Sorafenib Efficacy via MCL-1 and BIM in Hepatocellular Carcinoma Cells.Combinatorial chemistry & high throughput screening · 2023Article
- Knockdown of lncRNA TP53TG1 Enhances the Efficacy of Sorafenib in Human Hepatocellular Carcinoma Cells.Non-coding RNA · 2022Article
- AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.Cell death & disease · 2022Article
- Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy.Nature communications · 2022Article
- Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells.Theranostics · 2022Article
Corrections and comments
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Authors and funding
22 authors at 7 institutions in 4 countries.
Funding
Abstract
Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent "paradoxical" upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether "paradoxical" ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.
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Registered trials
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