ski or skii Lenvatinib is an orally available multi targeted

Lenvatinib is an orally available, multi-targeted tyrosine kinase inhibitor against VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT [11,12]. In a recent phase III trial for patients with previously untreated uHCC (REFLECT study), lenvatinib showed statistical non-inferiority of overall survival compared to sorafenib [13]. Furthermore, lenvatinib demonstrated significant and clinically meaningful improvement in objective response rate, progression-free survival, and time to progression compared with sorafenib. Our previous studies demonstrated that lenvatinib inhibits VEGF- and FGF-driven angiogenesis, and the tumor FGFR signaling pathways [11,12]. In particular, lenvatinib inhibits proliferation of HCC cell lines with activated FGF signaling pathways in vitro, and suppresses the FGF signaling pathways in preclinical human HCC xenograft tumors [14]. To understand the clinical activity of lenvatinib in uHCC, it is important to examine how inhibition of FGFR on tumor ski or skii contribute to the antitumor activity of lenvatinib in addition to antiangiogenic activity. Here, we evaluated the role of FGFR on the survival of HCC cells harboring an activated FGF signaling pathway by treatment with lenvatinib under nutrient-starved culture condition to mimic tumor microenvironments induced by angiogenesis inhibition.
Material and methods
Results
Discussion Although both Hep3B2.1-7 and HuH-7 cells overexpress FGF19, lenvatinib likely induced Hep3B2.1-7 and HuH-7 cell death via inhibition of FGFR1-3 in addition to FGFR4, It is reported that serum-starved and hypoxic culture condition induced expression of FGF8 subfamily members (FGF8, 17, and 18) in cultured HCC cell lines including Hep3B cells, and FGF8 family ligands show anti-apoptotic effects in serum-starved culture conditions in Hep3B cells [21]. Furthermore, FGF ligands are secreted by endothelial cells, tumor-associated fibroblasts, and tumor cells themselves, and might activate tumor FGF signaling pathways [22,23]. Given the complex crosstalk between FGF ligands from several sources, these insights might not be limited to FGF19-overexpressing HCC via FGFR4. A previous study under nutrient-full culture condition showed that FGFR4 knockdown suppressed proliferation of Hep3B2.1-7 and HuH-7 cells, but FGFR3 knockdown inhibited only the proliferation of Hep3B2.1-7 cells [24]; this finding suggests the high dependency of HuH-7 on the FGFR4 signaling pathway. Therefore, the observed higher response of HuH-7 cells to lenvatinib (has FGFR1-4 inhibitory activity) than to E7090 (a selective FGFR1–3 inhibitor) under nutrient-starved culture condition (Fig. 2A) might relate to the lack of inhibitory activity of E7090 against FGFR4 [11,17]. In addition, clear induction of Hep3B2.1-7 cell death with lenvatinib under nutrient-starved and hypoxic culture condition compared with E7090 (Supplementary Fig. 3A) suggested that the ability of FGFR1-4 inhibition by lenvatinib might be important to increase cell death of HCC with an activated FGF signaling pathway. Lenvatinib may show potent activity against survival of HCC cells under limited nutrients in tumor microenvironments induced by angiogenesis inhibition than subtype selective FGFR inhibitors, such as FGFR1-3 inhibitor or FGFR4 inhibitor. These results also suggest that superior objective response rate of lenvatinib (40.6%) compared to sorafenib (12.4%) by mRESIST with independent imaging review in the REFLECT phase 3 clinical trial [13] can be partially explained by inhibition of FGFR signaling pathways caused by lenvatinib in addition to VEGF signaling pathways.
Acknowledgements
Introduction Fibroblast growth factors 19 and 21 (FGF19 and FGF21) structurally belong to the FGF superfamily. In contrast to the classical FGFs that function in an autocrine/paracrine manner, these proteins have endocrine capabilities due to their low affinity for heparan-sulfate proteoglycans [1], [2], [3], [4]. Biochemically, they both require transmembrane β-Klotho (KLB) as a co-factor to facilitate signaling through various FGF receptors (FGFRs) [5], [6], [7], [8] and display overlapping metabolic pharmacology in rodents [9], [10], [11]. However, FGF19 is a potent inducer of hepatocellular carcinomas in mice [12], whereas FGF21 is not [13], [14].