sorafenib

Our study identified C/EBP-β as a key effector of the terminal pro-apoptotic ER stress response. While the direct clinical application of TM is limited by its systemic toxicity, these findings highlight the clinical translational potential of targeting the ER stress-C/EBP-β axis, offering a novel combination therapeutic strategy for patients with acquired sorafenib resistance.

For patients with high FLT1 expression, a combination therapy targeting this network-screened via molecular docking and dynamics simulations-may improve prognosis. This includes FLT1 inhibitors (Sorafenib, Regorafenib, Lenvatinib), supplemented by AKT1 inhibitors (Capivasertib) and VEGFA inhibitors (Bevacizumab) to suppress FLT1-associated malignant cell populations.

Our results show that YBX1 overexpression confers sorafenib resistance in HCC...In vivo studies demonstrated that inhibiting YBX1 with the small-molecule SU056 reduces tumor size. Thus, YBX1 is a promising target for extending drug resistance in HCC.

The treatment-dependent role of GRX1, which is protective in untreated tumors but can promote sorafenib resistance in treated cancers, establishes it as a critical ferroptosis-suppressing mediator and a potential therapeutic target for overcoming sorafenib resistance in RCC.

Additional analyses assessed endoglin/CD105 co-expression, paired primary-metastatic samples (n=41), and associations with adjuvant sorafenib therapy...As a conclusion, P21⁺/MCM2⁻ cell count is a robust biomarker that refines relapse risk stratification in ccRCC and identifies patients who may not benefit from adjuvant tyrosine kinase inhibitor therapy. High levels of these non-proliferative, senescent-like cells suggest tumour dormancy and a more favourable outcome without treatment.

P=N/A, N=941, Completed, Zhongda Hospital | Recruiting --> Completed | N=220 --> 941 | Trial completion date: Sep 2023 --> Sep 2025

P=N/A, N=1244, Completed, Zhongda Hospital | Recruiting --> Completed | N=474 --> 1244

Our study revealed that NDRG2 mediates the ubiquitination and degradation of ACC1 through recruiting COP1. Thus, targeting the NDRG2-ACC1 axis or its combination with sorafenib may be a novel potential strategy for HCC therapy.

In mice, significant reductions in the growth of subcutaneous tumors relative to controls were observed, and it is well-tolerated when compared to Doxorubicin and Sorafenib. Transcriptomics analysis using RNA-Seq revealed that genes involved in regulating cell death, cell proliferation, and cellular processes were enriched in a time- and dose-dependent manner. Overall, the cathepsin inhibitor appears to be a promising starting point for further investigation as an antiproliferative agent.

Since the approval of sorafenib in 2007, an increasing number of treatment regimens have demonstrated encouraging survival benefits in first-line treatment of advanced HCC...Our study is expected to inform clinical guidelines and support personalized therapeutic decisions for advanced HCC. https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420251126975.

Furthermore, drug sensitivity analysis linked SLC25A39 to a broader spectrum of pharmacological agents beyond sorafenib. Collectively, our findings not only reinforce SLC25A39 as a therapeutic target but, for the first time, reposition it as a potential modulator at the intersection of tumor metabolism, epigenetics, and immunology in HCC, offering a rationale for its inhibition, particularly combined with immunotherapy.

Several derivatives exhibited micromolar cytotoxic activity, with compound 14 emerging as the most active against HepG-2 cells (IC50 = 7.84 ± 0.5 µM), showing cytotoxic activity comparable to that of sorafenib (IC50 = 9.18 ± 0.6 µM) and demonstrating favorable selectivity toward normal WI-38 cells (IC50 = 67.75 ± 3.6 µM)...Molecular docking and MD simulations supported a stable binding mode within the VEGFR-2 active site. This integrated framework highlights compound 14 as a selectively active VEGFR-2-oriented anticancer candidate scaffold with a favorable selectivity profile, supported by experimental and computational analyses, warranting further lead optimization.