Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/ß­catenin pathway in xenograft models of hepatocellular carcinoma.

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.

Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma.

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.

Upregulated hPuf-A promotes breast cancer tumorigenesis.

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.