sorafenib

Overview

Sorafenib is a multi-kinase inhibitor that plays a critical role in the treatment of various cancers, particularly hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). It functions by inhibiting several receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), thereby disrupting tumor angiogenesis and cell proliferation. Sorafenib's mechanism of action also involves the induction of apoptosis in cancer cells, making it a vital therapeutic agent in oncology.

As the first-line therapy for advanced HCC, sorafenib has been pivotal in extending survival rates for patients. However, its effectiveness can be limited by the development of resistance mechanisms, which are a significant focus of ongoing research. Understanding these mechanisms is crucial for improving treatment outcomes and developing combination therapies that can enhance the efficacy of sorafenib.

Focus of Latest Publications

Recent publications have continued to examine sorafenib as both a therapeutic backbone and a sensitizing agent in combination strategies across multiple cancers. In hepatocellular carcinoma, several studies focused on overcoming sorafenib resistance by targeting stress-adaptive survival pathways. One report described clomipramine as a lysosomotropic partner intended to counter lysosomal sequestration of sorafenib and autophagy-associated chemoresistance in experimental HCC. Another study identified the endotrophin-CD44-STAT3 axis as a driver of tumor-stroma cross-talk and showed that this pathway promoted epithelial-mesenchymal transition, proliferation, and sorafenib resistance; disrupting the axis restored sorafenib sensitivity in a metabolic dysfunction-associated HCC model. A separate HCC study found that NAT10 inhibition reduced Nrf2 mRNA stability, increased oxidative stress, and sensitized HCC cells to sorafenib, highlighting redox homeostasis as a vulnerability linked to treatment response.

Other publications emphasized sorafenib resistance mechanisms in renal and lung cancer. In β2-adrenergic receptor-positive renal cell carcinoma, chronic stress-related catecholamines were shown to attenuate sorafenib efficacy by suppressing ferroptosis, with isoproterenol inducing resistance in vitro and in a mouse stress model; this effect was reversed by ADRB2 knockdown. In lung adenocarcinoma, sorafenib response was examined within a broader analysis of 3D chromatin architecture-related genes, with the study specifically noting sorafenib therapy in advanced LUAD as part of its resistance-focused investigation. Another mechanistic study showed that Aurora-A phase separation and stress granule assembly were triggered by sorafenib treatment, and that Aurora-A acted as a scaffold promoting sorafenib resistance through an RNA-binding, kinase-independent mechanism.

A substantial group of recent studies explored sorafenib in ferroptosis-based combination approaches. In triple-negative breast cancer, sorafenib was incorporated into exosomal, nanoparticle, and self-assembled delivery systems designed to enhance ferroptosis and improve tumor targeting. These platforms combined sorafenib with endogenous microRNAs, quercetin, or other pro-ferroptotic components to suppress GPX4, increase lipid peroxidation, disrupt mitochondrial function, and remodel the tumor microenvironment, with in vivo studies reporting antitumor efficacy and, in some cases, favorable biosafety. In colorectal cancer, sorafenib was paired with Atorvastatin or loaded into a mesoporous Fe-hematoporphyrin complex to intensify ferroptosis and photodynamic therapy, respectively; both studies reported enhanced oxidative damage, reduced tumor growth, and increased lipid peroxidation, although the Atorvastatin combination also raised toxicity concerns.

Sorafenib also appeared in comparative and clinical-context studies. In advanced HCC, it served as the reference first-line therapy in real-world and economic analyses, including a French cohort study of second-line practices after atezolizumab-bevacizumab and a cost-effectiveness comparison of finotonlimab plus bevacizumab versus sorafenib. A long-term follow-up of KEYNOTE-224 specifically referenced sorafenib-treated advanced HCC cohorts in evaluating pembrolizumab, while the CheckMate 9DW summary described nivolumab plus ipilimumab as outperforming lenvatinib or sorafenib in unresectable HCC. Across these publications, sorafenib was repeatedly used as a benchmark therapy, a partner in combination regimens, or a target whose efficacy was improved by modulating lysosomal trafficking, ferroptosis, oxidative stress, or tumor-stroma signaling.

Key Publications

• NEWJun Clomipramine potentiates sorafenib efficacy in experimental hepatocellular carcinoma by targeting lysosomal sequestration and modulating the cathepsin B/Bcl-2/Beclin-1 axis. (Molecular biology reports, 2026, PMID 42377685): "Lysosomal sequestration of chemotherapy drugs such as sorafenib decreases the effective concentration of chemotherapy at the target sites and leads to chemoresistance, also chemoresistance may arise from autophagy activation."
• NEWJun Pelvic desmoid fibromatosis: a diagnostic and therapeutic challenge. (BMJ case reports, 2026, PMID 42373202): "the patient has been under close follow-up and is receiving targeted therapy with oral sorafenib to prevent local progression."
• NEWJun Stress‑induced catecholamines attenuate sorafenib efficacy by inhibiting ferroptosis in β2‑adrenergic receptor positive renal cell carcinoma. (International journal of oncology, 2026, PMID 42359705): "Sorafenib, a molecular targeted agent for renal cell carcinoma (RCC), is involved in ferroptosis induction."
• NEWJun Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase. (Journal of medicinal chemistry, 2026, PMID 42286802): "In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib."
• NEWJun Second-Line Practices in the Era of Immunotherapy in HCC: The CHIEF Cohort. (JHEP reports : innovation in hepatology, 2026, PMID 42276189): "This study aimed to describe access to and outcomes of second-line (2L) treatments following atezolizumab-bevacizumab (AB) compared with sorafenib (Sor),"
• Jun 3D chromatin architecture-related genes orchestrate LUAD evolution and therapy resistance: insights from integrative machine learning and spatial single-cell mapping. (Functional & integrative genomics, 2026, PMID 42240917): "response to Sorafenib therapy in advanced LUAD"
• May Exploring Synergistic Potential of Sorafenib and Atorvastatin to Launch Apoptosis and Ferroptosis-driven Mixed Cell Death Mechanism in Colorectal Cancer. (AAPS PharmSciTech, 2026, PMID 42204072): "The present investigation explores the combined therapy of Sorafenib (SOR) and Atorvastatin (ATST) to induce a dual cell death mechanism, specifically ferroptosis and classic apoptosis, in colon cancer cells."
• Jul Synthesis and biological evaluation of thiophene based oxadiazole derivatives as promising anticancer agents against liver cancer. (Pakistan journal of pharmaceutical sciences, 2026, PMID 42170959): "Clinical use of the first-line drug sorafenib is limited due to drug resistance and severe adverse effects."
• Jul Nano-scaffolds for enhanced in-vitro and in-vivo anti-VEGFR drug delivery. (Pakistan journal of pharmaceutical sciences, 2026, PMID 42170960): "Sorafenib (SB) is a receptor tyrosine kinase inhibitor, currently marketed as an oral dosage form."
• May Economic evaluation of finotonlimab plus bevacizumab as first-line therapy for advanced hepatocellular carcinoma. (PloS one, 2026, PMID 42133639): "To compare the cost-effectiveness of dual-agent group (finotonlimab combined with a bevacizumab biosimilar) (SCT510) versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HCC) from the perspective of the Chinese healthcare system."