FGF19 expression

Overexpression studies in transgenic mice have further revealed roles in not only ameliorating metabolic diseases but also in promoting hepatocyte proliferation and tumorigenesis. This review summarizes the gene and protein structure of FGF19/15, its expression patterns, phenotypes in mutant models, and implication in human diseases, providing insights into potential therapeutic strategies targeting the FGF19 signaling pathway.

This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

All patients received carboplatin and paclitaxel given every three weeks for six cycles and were randomized to bevacizumab. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

Genomic analysis of patient samples from The Cancer Genome Atlas (TCGA) confirmed that a segment of HCC patients harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.

Co-activation of Met & FGF19 occurs in a significant subset of HCC patients with co-expression leading to HCC development in mice. This Met/FGF19 preclinical model provides an improved platform to test various targeted and immunotherapies.

FGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.

Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Hosted by NCCN Oncology Research Program (ORP)

Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.

Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Our data demonstrate that KFS1-containing plant extracts modulate expression and activity of FXR in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, such extracts have significant therapeutic and commercial potential to be developed as a novel first-in-class "FXR-targeted nutraceutical" for treatment and prevention of common intestinal disorders.

In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing.

This study proves that melatonin suppresses SCC-15 cells invasion and migration through blocking the FGF19/FGFR4 pathway, which enriches our knowledge on the anticancer effects of melatonin. Blocking the FGF19/FGFR4 pathway by melatonin could be a promising alternative for OSCCs prevention and management, which would facilitate further development of novel strategies to combat OSCCs.

Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.

BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line...Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.

We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.

Earlier studies reporting reductions in inflammation and fibrosis utilized AAV serotype 9, a vector with broader tropism than the AAV8 used in this experiment that has primary tropism for hepatocytes. Future studies will examine these questions and compare effects on disease amelioration with novel candidates identified by our in vivo, high throughput, screening platform.

Our results support the hypothesis that hepatoblastoma depends on receptor tyrosine kinase signaling through MEK, in addition to constitutive Wnt pathway activation, for cell cycle progression and proliferation. We identify paracrine FGF19 signaling as a potential mechanism by which a subset of hepatoblastomas may fuel their own growth.

The expression of FGF19 is significantly upregulated in NSCLC, and the overexpression of FGF19 is correlated with poor OS, especially in lung adenocarcinoma (LUAD) cases. FGF19 might serve as a potential biomarker for predicting poor OS in NSCLC patients.

Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays... FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.

Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

Tumor-bearing mice were then treated with lenvatinib (LEN), or sorafenib (SOR), or vehicle until moribund. ST6GAL1 is a tumor-derived secreted protein downstream of FGF19 and may be a useful serum biomarker for identification of patients with FGF19-driven HCC who may benefit from LEN therapy.

P1/2, N=80, Recruiting, EverNov Medicines (Zhuhai Hengqin) Co., Ltd