FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…Fibroblast growth factor 19 (FGF19) is a driver oncogene that is amplified in approximately 14% of HCC patients and overexpressed in 50% of HCC patients, making the FGF19 gene a novel potential target for the treatment of HCC [ 340 , 341 ]. Combined treatment of FGF401 and vinorelbine can synergistically inhibit the growth of HCC tumor models with high expression of FGF19 and promote cell apoptosis, thereby prolonging the overall survival of mice and improving the antitumor activity [ 342 ]. Recently, the combination of vinorelbine and lenvatinib showed a strong synergism in anaplastic thyroid cancer cells, associated with modulating ABCB1 transporter, reduced CSF-1 expression, with an inhibition of Akt/GSK3β/PRAS40 pathway, and a decrease in the phosphorylation of Src.…”

Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma

“…It also converts the immunosuppressive microenvironment to an immunosupportive one, allowing greater intra-tumoral immune cell in ltration, resulting in superior tumor regression compared with monotherapy. Taken together, our data provide the rationale to evaluate combination in gratinib/FGF401 in HCC patients with high FGFR2/3 (~ 17%) [12] or FGF19 (~ 12%) expression [14]. xenografts (eight mice per group) were administered vehicle and four combinations (15:30, 10:20, 7.5:15, and 5:10 in gratinib: FGF401) for 15 days.…”

“…FGF401 is a selective FGFR4 inhibitor that has shown potent antitumor activity in patient derived xenograft (PDX) models that are positive for FGF19 [13,14]. FGF401 also reduced tumor hypoxia, induced blood vessel normalization, prolong the OS of mice bearing in a FGF19-dependent manner [14].…”

Development of a prognostic signature of patients with esophagus adenocarcinoma by using immune-related genes

“…Therefore, this makes it possible to develop some FGFR4-specific inhibitors to increase specificity and reduce the toxicity of FGFR targeted therapy. Moreover, some FGFR4 specific inhibitors (such as FGF401, BLU-554 and H3B-6527) combined with other treatments are also indispensable for improving clinical treatment effects [41][42][43]. FGF401 can act synergistically with vinorelbine to inhibit tumor growth and promote tumor apoptosis by inhibiting the FGF19/FGFR-4 signaling pathway [41].…”