Real-world efficacy and safety of TACE-HAIC combined with TKIs and PD-1 inhibitors in initially unresectable hepatocellular carcinoma.

BACKGROUND: Local treatment may function synergistically with immunotherapy and targeted agents. This study aimed to assess the effectiveness and safety of transcatheter arterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and programmed death-1 (PD-1) inhibitors in patients with initially unresectable hepatocellular carcinoma (uHCC). METHODS: A retrospective study was conducted on patients diagnosed with initially uHCC who received combined treatment of TACE-HAIC combined with TKIs and PD-1 inhibitors from July 2020 to February 2023. The primary endpoints were overall survival (OS) and progression free survival (PFS) and adverse events (AEs). Objective response rate (ORR), disease control rate (DCR) and conversion surgery rate (CSR), whereas the secondary endpoints. RESULTS: After screening, a total of 62 patients were selected for this study. The overall median OS was 18.2 (95% CI 16.24-20.16) months and median PFS was 9.2 (95% CI 7.24-11.16) months. Based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and RECIST v1.1 criteria, ORR was 67.7% (42/62), and the DCR was 90.3% (56/62), the CSR was 27.4% (17/62). The most common treatment-emergent adverse events (TEAEs) were transaminitis (56.4%, 35/62), nausea and vomiting (43.5%, 27/62), thrombocytopenia (37.1%, 23/62), abdominal pain (33.9%, 21/62), and fever (33.9%, 21/62). CONCLUSIONS: TKIs combined with PD-1 inhibitors plus TACE-HAIC therapy represents an effective and tolerable treatment option in patients with uHCC. Patients undergoing surgery after combination therapy may have survival benefits.

TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs.

For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC.

RNF26 Promotes Pancreatic Cancer Proliferation by Enhancing RBM38 Degradation.

OBJECTIVES: RING finger protein 26 (RNF26) plays an essential role in determining malignant tumor growth, whereas the role of which in pancreatic cancer (PC) has not been reported. This study aimed to investigate the role of RNF26 in PC cells. METHODS: The Gene Expression Profiling Interactive Analysis was applied to study the role of RNF26 in malignant tumors. The in vitro or in vivo cell proliferation assays were used to investigate the role of RNF26 on the PC. The protein-protein interaction network analysis was used to search the binding partner of RNF26. The Western blot was used to reveal whether RNF26 promoted RNA binding motif protein-38 (RBM38) degradation in PC cells. RESULTS: The Gene Expression Profiling Interactive Analysis tool showed that RNF26 was overexpressed in PC. Repressing RNF26 expression decreased PC cells growth, but overexpression of RNF26 increased PC proliferation. Furthermore, we demonstrated RNF26 degraded RBM38 to promote PC cell proliferation. CONCLUSIONS: RNF26 was abnormally increased in PC, and upregulated RNF26 was correlated with a poor prognosis. RNF26 enhanced PC proliferation by inducing RBM38 degradation. We identified a novel RNF26-RBM28 axis involved in the progression of PC.