This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

Our findings suggest that the mutual validation of big data analysis and functional experiments may facilitate the precise identification and definition of biomarkers, and our m6A risk models may have the potential to guide personalized chemotherapy, targeted treatment, and immunotherapy decisions in HCC.

The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.

These results reveal that the MR, specifically in EC but not in SMCs, is necessary for VEGFRi-induced renal and vascular injury. While ineffective at lowering SBP, these data suggest potential therapeutic benefits of MR antagonists, like spironolactone, to protect the vasculature and the kidneys from VEGFRi-induced injury.

Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines 19 and 31 were found to be more cytotoxic than sorafenib (SOR)...Furthermore, compounds 19 and 31 were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.

Our study concludes that sorafenib-induced METs inhibit the ferroptosis of tumor cells, suggesting that targeting the IL4/PADI4/METs axis in HCC could reduce or prevent sorafenib resistance.

Overexpressing MARK1 suppressed sorafenib-induced proliferation in resistant cells, while co-overexpression of MARK1 and POTEE reversed this effect. MARK1 potentially restrains HCC progression and enhances sorafenib resistance by negatively modulating POTEE expression, highlighting its significance as a therapeutic target in HCC treatment.

P2, N=25, Completed, NovoCure Ltd. | Unknown status --> Completed

In summary, the MIRGPI signature we developed is a reliable marker for the prediction of prognosis and treatment response, and is important for the prognostic assessment and individualized treatment of HCC.

Moreover, the elevated expression of Pim-3, resulting from the absence of miR-936 enhances sorafenib resistance in liver cancer by inhibiting cell ferroptosis. Pim-3 can be regarded as a target in the treatment of sorafenib-resistant liver cancer.

Compound 20b presents as a promising anti-proliferative agent targeting VEGFR-2. Also, this comprehensive investigation underscores the potential of 2,3-dihydro-1,3,4-thiadiazole derivatives as promising candidates for further development in anti-cancer research.

Allo-HSCT immediately following complete remission could improve outcomes for young adults diagnosed with FLT3-ITD-positive AML. However, we found no statistical difference in the overall response rate (ORR) and clinical outcome between sorafenib combined with chemotherapy and chemotherapy alone.

Drug sensitivity analysis showed significantly higher IC50 values for 5-fluorouracil, gemcitabine, and sorafenib in patients with low MRTO4 expression than in those with high MRTO4 expression. MRTO4 acts as an independent prognostic and immunological biomarker and is correlated with clinical stage, tumor grade, and drug sensitivity in HCC. It may serve as a putative therapeutic target and potential biomarker for prognosis of HCC.

In this study, a multifunctional nanozyme, MMSR-pS-PEG, is designed and fabricated by modifying poly (ethylene glycol) grafted phosphorylated serine (pS-PEG) on mesoporous hollow MnMoOx spheres, followed by loading sorafenib (SRF) into the pores...As a ferroptosis inducer, SRF restrains the system xc - and indirectly inhibits glutathione synthesis, synergistically interacting with the nanozyme to stimulate ferroptosis by promoting lipid peroxidation and accumulation and the downregulation of glutathione peroxidase 4. These results provide valuable insights into the design of enzymatic therapy with high performance and highlight a promising approach for the synergism of ferroptosis and enzymatic tumor therapy.

Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib...The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

Conclusion Activation of TLR3 can enhance the antitumor effect of sorafenib on HCC. The combination of a TLR3 activator and sorafenib may be a new strategy for the treatment of HCC.

A marked reduction in the intrinsic tryptophan fluorescence of tubulin, a concentration-dependent elevation of anilinonaphthalene sulfonate-tubulin complex fluorescence, electron micrographs of deformed in vitro-assembled microtubules, and disrupted and hyper-stabilized cellular microtubules evinced the ability of SF to target tubulin and disrupt cellular microtubules at its IC50 for cell viability. Molecular docking and molecular dynamic simulations positioned the drug between the α and β subunits of tubulin with considerable stability (ΔGbind, -31.43 kcal/mol), suggesting that drug-induced perturbation of tubulin could contribute to this mode of cell death.

Moreover, DNASE1L3-induced PANoptosis augmented the activation of anti-tumor immunity within the tumor microenvironment (TME), thereby enhancing the efficacy of the combination therapy involving sorafenib and PD-1 mAb. Our findings offer valuable insights into the mechanisms underlying DNASE1L3's role in sorafenib sensitivity and position DNASE1L3 as a promising predictive biomarker and target for improving outcomes in combination therapy for HCC.

In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC.

The combination of small particle DEB-TACE and sorafenib significantly improves both short- and long-term outcomes in the treatment of unresectable liver cancer while preserving liver function.

SYNE1 contributes to the modulation of sorafenib resistance in ccRCC cells through interacting with BIN1. Decitabine treatment enhances expressions of these two proteins to improve TKI response, suggesting a potential strategy for counteracting resistance and bettering patient outcomes.

CVR/SOR is a powerful combination for tumor repression and enhancing SOR efficiency in HCC by modulating FGL1. Moreover, CVR/SOR might exert the aforementioned effects through HIF-1α/STAT3/FGL1 pathway.

P1, N=105, Recruiting, BeiGene | Phase classification: P1b --> P1

The nanoplatform, IS@ATF, was designed that self-assembled by loading the NO donor L-arginine (L-Arg), ferroptosis inducer sorafenib (SRF), and indocyanine green (ICG) onto tannic acid (TA)-Fe3+‒metal-phenolic networks (MPNs) modified with hydroxyethyl starch...In addition, the nanoplatform showed significantly improved tumor therapeutic efficacy and anti-metastasis efficiency. This work thus demonstrated that utilizing NO boost-GSH depletion to enhance ferroptosis induction is a feasible and promising strategy for cancer treatment.

The quinazoline based glycosyl-1,2,3-triazoles 10-13 with free hydroxy sugar moiety revealed excellent potency against (IC50 range = 5.70-8.10 µM, IC50 Doxorubicin = 5.6 ± 0.30 µM, IC50 Erlotinib = 4.3 ± 0.1 µM)...The hydroxylated glycosides incorporating triazole and quinazoline system 11 and 13 with N-methyl substitution of quinazolinone, gave excellent potency against EGFR (IC50 = 0.35 ± 0.11 and 0.31 ± 0.06 µM, correspondingly) since glycoside 13 revealed comparable IC50 (3.20 ± 0.15 µM) to sorafenib against VEGFR-2...Additionally, the latter derivative may trigger apoptosis, as indicated by a significant increase in apoptotic cells. Furthermore, molecular docking was simulated to make an obvious validation and comprehension acquirement of the binding's characteristics also attractions among the most forceful compounds side by side with their aimed enzymes.

P1, N=131, Completed, BeiGene | Phase classification: P1a/1b --> P1

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

Further subgroup Cox analyses revealed that the lack of combination TACE therapy was an independent risk factor for OS in both the vascular invasion group and the group with both risk factors. In conclusion, for patients with advanced HCC receiving sorafenib, the addition of TACE may enhance long-term survival, particularly in those with vascular invasion.

When combined with the anti-HCC drug sorafenib, STR-V-53, showed greater in vivo efficacy...Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.

Interestingly, the IC50 of compound (6c) (7.2 µM) exhibited better activity than that of Sorafenib (positive control) (9.98 µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site.

Moreover, the SF further enhances therapeutic efficacy by inducing autophagy in response to energy deprivation, as indicated by the reduced levels of HIF-1α, p62, along with increased levels of ROS and LC3-Ⅱ/Ι. This biomineralization-based nanoenzyme exhibits strong anti-tumor characteristics, offering a novel strategy for overcoming challenges in liver cancer treatment.

Combination therapy with Sorafenib and TACE is effective for patients with advanced PLC, reducing AFP-L3 and DCP levels and improving patient survival rates. Additionally, higher levels of serum AFP-L3 and DCP are associated with poor prognosis.

In summary, our study unveils the potent role of DDX11-AS1 as an enhancer of sorafenib resistance, inhibiting sorafenib-induced ferroptosis through the activation of the Nrf2-Keap1 pathway in HCC. These findings offer a promising therapeutic strategy to overcome resistance and effectively treat HCC.

Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.

Additionally, this model was successfully used to assess the antimetastatic efficacy of sorafenib. In conclusion, our results demonstrate that the established spontaneous metastatic xenograft model better reflects liver cancer metastasis and can be utilized to assess the efficacy of anticancer drugs for liver cancer.

DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.

Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.

We find that increased autophagy is accompanied by ferroptosis in USP24 overexpressed HCC cells and USP24 increases the susceptibility of HCC to sorafenib. Collectively, this study highlights the critical role of USP24 in regulating autophagy-dependent ferroptosis by decreasing Beclin1 ubiquitination, suggesting that targeting USP24 may be a strategy for treating HCC.

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Aug 2024 --> Nov 2024

Further analysis on A375 and Mel501 cell lines expressing BRAFV600E revealed that compound 9s has a potent growth inhibitory activity with IC50 of 0.7 and 1.5 µM, respectively, in reference to sorafenib (IC50 = 8.7 and 0.3 µM, respectively)...Noteworthy, the examined candidates demonstrated a higher selectively towards BRAFV600E over BRAFWT highlighting their promising optimization for treating BRAFV600E expressing cancers. Molecular docking and molecular dynamics simulations in the inactive DFG-out kinase domain of BRAFWT/V600E protein kinases confirmed the planned design strategy.

In conclusion, Brusatol improves the efficacy of sorafenib by inducing ferroptosis via hindering Nrf2 signaling activation in HCC.