sorafenib

We analyzed 523 adults with FLT3-ITD AML in first complete remission who underwent allo-HCT between 2011 and 2023 in 13 German transplant centers participating in the national DRST registry; 22% received FLT3i maintenance (sorafenib 49%, midostaurin 37%, gilteritinib 5%, unknown 9%). Sorafenib maintenance (n=50) demonstrated superior efficacy with 5-year OS of 85% versus 62% (HR 2.979, p=0.0045) and RFS of 84% versus 55% (HR 2.771, p=0.0043) compared to no maintenance. These real-world findings, while limited by the retrospective design and potential selection bias, align with randomized trial data and support the use of FLT3i maintenance as part of post-transplant care for FLT3-ITD AML.

P=N/A, N=324, Completed, First Affiliated Hospital, Sun Yat-Sen University

Our findings demonstrate that RPL28 contributes to sorafenib resistance in HCC by upregulating CDC6, contributing to tumor proliferation and drug resistance. The newly identified RPL28-CDC6 axis represents a novel mechanism of resistance and a potential therapeutic target to overcome treatment limitations in HCC.

P=N/A, N=453, Active, not recruiting, Bayer | Trial completion date: Nov 2025 --> Sep 2026

The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction. NCT05068752.

VEGF inhibitors, such as bevacizumab and VEGFR-TKIs (e.g., sorafenib, sunitinib), significantly elevate the risk of ATEs, with hypertension and proteinuria as common comorbidities. BCR-ABL-TKIs, especially nilotinib and ponatinib, are linked to rapid-onset PAD, even in patients without prior cardiovascular risk factors...Hormonal therapies, including tamoxifen and androgen deprivation therapy, also contribute to ATEs through metabolic and vascular mechanisms...Monitoring and prevention strategies, such as regular cardiovascular risk assessments, lipid management, and arterial ultrasound surveillance, are critical for high risk patients. Multidisciplinary onco-vascular teams are essential to mitigate these risks and optimize patient outcomes.

We synthesize recent advances linking these molecular axes to ferroptosis pathways, discuss their crosstalk in sorafenib-resistant HCC, and underscore emerging therapeutic strategies that leverage pharmacological or radiotherapeutic targeting of these mechanisms. A deeper understanding of this regulatory network may inform rational combination therapies aimed at resensitizing advanced HCC to sorafenib.

Mechanistically, COPG1 depletion induced Golgi disruption and ER stress, increased ROS production, and suppressed PI3K-AKT signaling, thereby sensitizing cells to sorafenib and doxorubicin. Collectively, this pan-cancer analysis reveals the context-dependent roles of coatomer subunits and identifies COPG1 as a novel oncogenic driver and potential therapeutic target in HCC, mediating chemoresistance through redox modulation and PI3K-AKT pathway inhibition.

Among these, 2'-Hydroxy-Delta (9)-THC and Ajulemic Acid combined favorable multi-target binding with superior predicted pharmacokinetic properties compared with other cannabinoids and reference inhibitors (lapatinib, motesanib, and sorafenib). Toxicity predictions classified all compounds as moderately toxic, with Ajulemic Acid showing a comparatively more favorable safety profile. These findings do not demonstrate biological inhibition and should be interpreted strictly as hypothesis-generating computational evidence, providing a rational framework for future in vivo and in vitro validations.

The combination of nutrient restriction and Sorafenib significantly enhanced anti-tumor efficacy both in vivo and in vitro. Mechanistically, nutrient restriction potentiated Sorafenib-induced ferroptosis via the NRF2/HO-1/GPX4 pathway in HCC cells.

Anemarrhenone A (AA), with IC50 values of 5.19 ± 1.25 μM for Hep3B cells and 4.02 ± 1.13 μM for HepG2 cells, exhibited anti-HCC activity comparable to that of sorafenib (IC50 of 5.63 ± 0.27 μM for Hep3B cells and 2.34 ± 0.28 μM for HepG2 cells). ALDH3A1 emerged as a direct functional target through which AA exerted its anti-HCC activity. This research revealed a potential tumor suppressive pathway mediated by AA and provided a strategic approach against HCC.

These findings demonstrate that acquired sorafenib resistance in HCC is associated with a stable NRF2-driven transcriptional and metabolic reprogramming that enhances antioxidant capacity, suppresses ferroptosis and promotes tumor cell survival. Targeting NRF2-regulated redox metabolism may therefore represent a promising strategy to overcome therapeutic resistance in HCC.