ABSTRACT
Mutations affecting the Wnt/ßcatenin pathway have been identified in 2640% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/ßcatenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/ßcatenin signaling in HCC models were evaluated. A ßcatenin mutant and ßcatenin wildtype HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/ßcatenin signaling. Apoptosis, cell proliferation and ßcatenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naïve and sorafenibresistant HCC models. Despite similar total ßcatenin levels, significant reductions in phosphorylated (p)RanBP3 Ser58, pßcatenin Tyr142, active ßcatenin and ßcatenin target genes were observed in sorafenib/refametinibtreated tumors. Greater levels of ßcatenin in sorafenib/refametinibtreated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/ßcatenin pathway and suppressed Wnt3Ainduced plowdensity lipoprotein receptorrelated protein 6 Ser1490, pRanBP3 Ser58 and pßcatenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naïve and sorafenib resistant HCC tumors in association with active suppression of ßcatenin signaling regardless of ßcatenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Wnt Signaling Pathway/drug effects , Animals , Benzimidazoles/administration & dosage , Diphenylamine/administration & dosage , Diphenylamine/analogs & derivatives , Humans , Male , Mice , Mice, SCID , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Sorafenib/administration & dosage , Sulfonamides/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Pyrimidines/therapeutic use , Animals , Blood Vessels/drug effects , Carcinoma, Hepatocellular/secondary , Liver Neoplasms/pathology , Male , Mice , Mice, SCID , Phenylurea Compounds/pharmacology , Pyrimidines/pharmacologyABSTRACT
hPuf-A is a member of RNA-binding PUF family that regulates mRNA translation. Redistribution of hPuf-A from the nucleolus to the nucleoplasm upon genotoxic stress modulates the poly(ADP-ribosyl)ation activity of PARP-1. Here, we report a novel function of hPuf-A involved in promoting breast cancer progression. Immunohistochemical studies showed higher expression levels of hPuf-A in stage I, II, III, and IV breast cancer specimens in contrast with those of hPuf-A in ductal carcinoma in situ. The presence of hPuf-A is highly associated with colony formation capacities in breast cancer T47D and MDA-MB-231 cells. Xenograft growth of hPuf-A-silenced and hPuf-A overexpressing MDA-MB-231 cells in nude mice was substantially in concert with colony formation capacities. This promoting effect of hPuf-A in tumorigenesis might be correlated with the regulation of its associated mRNAs, such as RbAp48 and DDX3. Collectively, hPuf-A may have diagnostic values in breast cancer progression.