sorafenib
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting sorafenib (sorted by publication date).
Recent research has extensively investigated mechanisms of sorafenib resistance and developed combination strategies to enhance therapeutic efficacy across multiple cancer types. A key resistance mechanism involves lysosomal sequestration of sorafenib, which reduces drug concentration at target sites; combining sorafenib with the lysosomotropic agent clomipramine potentiated efficacy in hepatocellular carcinoma by modulating the cathepsin B/Bcl-2/Beclin-1 axis [42377685]. In renal cell carcinoma, chronic stress-induced catecholamines were shown to attenuate sorafenib efficacy by inhibiting ferroptosis through β2-adrenergic receptor signaling, an effect reversible by ADRB2 knockdown [42359705]. Additional resistance mechanisms identified include Aurora-A-mediated stress granule assembly, which confers sorafenib resistance through RNA-binding scaffolding independent of kinase activity [42008675], and the NAT10-Nrf2 mRNA stability axis, which sustains antioxidant capacity in hepatocellular carcinoma; NAT10 inhibition markedly sensitized HCC cells to sorafenib [41692399]. The endotrophin-CD44-STAT3 signaling axis was also identified as driving sorafenib resistance and epithelial-mesenchymal transition in hepatocellular carcinoma through tumor-stroma crosstalk [41671381].
To overcome these resistance mechanisms, multiple combination approaches have demonstrated synergistic activity. Sorafenib combined with Atorvastatin induced dual ferroptosis and apoptosis in colorectal cancer cells with ~80% tumor growth inhibition in vivo, though safety concerns were noted [42204072]. Carbonic anhydrase IX/XII inhibitors enhanced the antiproliferative effects of sorafenib in breast and pancreatic cancer cells under both normoxic and hypoxic conditions [42059120]. In sorafenib-treated hepatocellular carcinoma patients, pembrolizumab monotherapy demonstrated durable antitumor activity with long-term follow-up extending to approximately 7 years [41770235]. Additionally, combining saquinavir with sorafenib exhibited synergistic antitumor activity in hepatocellular carcinoma by inducing pyroptosis through the OTUD5-JAK1-GSDME axis [41687749].
Innovative drug delivery systems have been developed to enhance sorafenib bioavailability and therapeutic targeting. A bioinspired exosomal nanoplatform (Sor@AKAExo) incorporating sorafenib and endogenous microRNAs achieved spatiotemporal codelivery to triple-negative breast cancer, synergistically inducing ferroptosis and apoptosis while remodeling the immunosuppressive tumor microenvironment [42030227]. A mesoporous Fe-hematoporphyrin complex loaded with sorafenib demonstrated synergistic photodynamic therapy and ferroptosis in colorectal cancer by downregulating SLC7A11 and depleting glutathione [42011059]. Sorafenib-quercetin nanoparticles were shown to overcome hypoxic and acidic tumor microenvironments in triple-negative breast cancer by suppressing HIF-1α and hexokinase II, thereby enhancing ferroptosis [41946426]. A GSH-responsive nanoprodrug coupling sorafenib with rhein and ferrocene achieved synchronous release in tumor cells, triggering combined ferroptosis and apoptosis in triple-negative breast cancer [41650740].
Sorafenib continues to be evaluated across diverse cancer types and clinical settings. In hepatocellular carcinoma, real-world data from the CHIEF cohort described second-line treatment access and outcomes following atezolizumab-bevacizumab compared with sorafenib [42276189], while economic analyses compared the cost-effectiveness of newer immunotherapy combinations against sorafenib as first-line therapy [42133639]. The CheckMate 9DW study demonstrated superior efficacy of nivolumab plus ipilimumab over lenvatinib or sorafenib in unresectable hepatocellular carcinoma, with longer overall survival and improved quality of life [41981891]. A novel PC inhibitor (CIB-Q22) exhibited comparable antitumor efficacy to sorafenib in hepatocellular carcinoma but with improved pharmacokinetic properties and favorable safety [42286802]. In clear cell renal cell carcinoma, FLT1-mediated epithelial-endothelial crosstalk was identified as driving malignancy, with sorafenib recommended as part of combination therapy for high FLT1-expressing tumors [41999263]. Sorafenib was also evaluated in rare malignancies, providing effective targeted therapy for residual pelvic desmoid fibromatosis with imaging evidence of disease reduction [42373202]. Notably, sorafenib demonstrated unexpected broad-spectrum antibacterial activity against Streptococcus pneumoniae, including multidrug-resistant strains, by inhibiting the bacterial serine/threonine kinase StkP, suggesting potential for drug repurposing beyond oncology [42300766].