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The objective of this study was to determine the effect of early lactation body condition (BC) loss in multiparous dairy cows on serum lipids and the effect of these changes on oocyte and cumulus cell transcriptomes. Body condition loss in dairy cattle after parturition is associated with reduced fertility and increased pregnancy loss. The complex interplay between BC, nutrition, dry matter intake, milk production, and time of calving has presented a barrier to understanding mechanisms leading to reduced fertility. We identified cows that lost BC (L group; n = 10) or maintained or gained BC (M/G group; n = 8) during the first 27 to 33 d in milk and investigated changes in serum fatty acids and oocyte and cumulus cell transcriptomes at 75 to 81 d in milk. The L group had increased serum levels of nonesterified fatty acids and mead acid, and reduced serum levels of petroselaidic acid and behenic acid. Transcriptome analyses revealed 38 differentially expressed genes (DEG) in oocytes and 71 DEG in cumulus cells of L (n = 3) compared with M/G group (n = 3). Network analysis connected serum fatty acid changes to downstream effects including reduced inflammatory response and mitochondrial membrane depolarization, increased production of reactive oxygen species, and functions related to fatty acid metabolism and cytoplasmic organization in oocytes. These effects were associated with predicted effects on signaling in oocytes through calcium, insulin, O-GlcNAcase (OGA), fibroblast growth factor receptor 4 (FGF4R), peroxisome proliferator activated receptor gamma coactivator 1 α (PPARGC1A), and phospholipase D2 (PLD2) pathways, with a connection to the cumulus cell via calcium signaling. These results connect BC loss following parturition to changes in serum lipid levels, and changes potentially affecting oocyte quality; thus, these results provide new insight into mechanism of reduced fertility.

Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.

INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for the treatment of hepatocellular carcinoma (HCC) with aberrant FGFR4 signaling because of its important role in HCC progression and development. Several FGFR4 inhibitors are under clinical development. Using a 7-azaindole scaffold, we discovered a series of novel selective and covalent FGFR4 inhibitors by performing a structure-based design approach. Representative compounds

Thyroid receptor-interacting protein 13 (TRIP13), a protein of the AAA-ATPase family, is upregulated in various human cancers, including colorectal cancer (CRC). This study focused on the inhibition of TRIP13-induced CRC progression and signalling by DCZ0415, a small molecule targeting TRIP13. It demonstrated potent antitumour activity in TRIP13-deregulated cancer cell lines, regardless of their p53, KRAS, BRAF, epidermal growth factor receptor or microsatellite instability status. The treatment of CRC cells with DCZ0415 resulted in decreased cell proliferation, induced cell cycle arrest in the G2-M phase and increased apoptosis. DCZ0415 diminished xenograft tumour growth and metastasis of CRC in immunocompromised mice. DCZ0415 reduced expression of fibroblast growth factor receptor 4 (FGFR4), signal transducer and activator of transcription 3 (STAT3), and proteins associated with the epithelial-mesenchymal transition and nuclear factor kappa B (NF-κB) pathways in cells and xenografts exhibiting high expression of TRIP13. Additionally, DCZ0415 decreased cyclin D1, β-catenin and T-cell factor 1, leading to the inactivation of the Wnt/β-catenin pathway. In a syngeneic CRC model, DCZ0415 treatment induced an immune response by decreasing PD1 and CTLA4 levels and increasing granzyme B, perforin and interferon gamma. In sum, DCZ04145 inhibits the TRIP13-FGFR4-STAT3 axis, inactivates NF-κB and Wnt/β-catenin signalling, activates antitumour immune response and reduces the progression and metastasis of CRC. This study provides a rationale to evaluate DCZ0415 clinically for the treatment of a subset of CRCs that exhibit dysregulated TRIP13 and FGFR4.

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound

Highlights • GNF-7, a multi-targeted kinase inhibitor, is highly potent against FGFR4. • GNF-7 and SIJ1263 are highly potent on Ba/F3 cells with wtFGFR4 or mtFGFR4. • GNF-7 and SIJ1263 are highly potent on HCC cells with FGFR4 activation. • GNF-7 and SIJ1263 strongly block FGFR signaling and induce apoptosis in HCC cells. • GNF-7 and SIJ1263 strongly suppress migration/invasion/AIG of HCC cells., Hepatocellular carcinoma (HCC) is disease with a high mortality rate and limited treatment options. Alterations of fibroblast growth factor receptor 4 (FGFR4) has been regarded as an oncogenic driver for HCC and a promising target for HCC therapeutics. Herein, we report that GNF-7, a multi-targeted kinase inhibitor, and its derivatives including SIJ1263 (IC50 < 1 nM against FGFR4) are highly potent FGFR4 inhibitors and are capable of strongly suppressing proliferation of HCC cells and Ba/F3 cells transformed with wtFGFR4 or mtFGFR4. Compared with known FGFR4 inhibitors, both GNF-7 and SIJ1263 possess much higher (up to 100-fold) anti-proliferative activities via FGFR signaling blockade and apoptosis on HCC cells. Especially, SIJ1263 is 80-fold more potent (GI50 = 24 nM) on TEL-FGFR4 V550E Ba/F3 cells than BLU9931, which suggests that SIJ1263 would be effective for overriding drug resistance. In addition, both substances strongly suppress migration/invasion and colony formation of HCC cells. It is worth noting that SIJ1263 is superior to GNF-7 with regards to the fact that activities of SIJ1263 are higher than those of GNF-7 in all assays performed in this study. Collectively, this study provides insight into designing highly potent FGFR4 inhibitors capable of potentially overcoming drug-resistance for the treatment of HCC patients.

The aim: Evaluating the role SNP rs351855 of (FGFR4) gene and estimating the serum concentration of Visfatin cytokine and (HMGB-1) protein in AC patients and in healthy control blood samples. Materials and methods: Blood samples were collected from 35 patients and 35 healthy controls, and then the serum was used for ELISA test, another each 2 ml blood were used for DNA extraction and rs351855 of (FGFR4) PCR assay. Results: there was no significant difference in mean HMG and mean visfatin among (FGFR4) rs351855 genotypes in patients and control group. There was no significant difference in mean (HMG) among (FGFR) rs351855 genotypes in patients` group (p = 0.923); there was also no significant difference in mean visfatin among FGFR rs351855 genotypes in patients` group (p=0.161) rs351855 genotypes showed that the homozygous GG, heterozygous A/G and homozygous AA. Despite these minor differences there was no significant variation (p = 0.323), also no significant difference in frequency distribution of individuals according to FGFR rs351855 G>A SNP polymorphism between patients` and control groups (p = 0.454). The same was applied to recessive and allelic analysis p>0.05. Conclusions: There was no role for (FGFR4) rs351855G/A SNP in disease susceptibility to acute cholecystitis in Iraqi patients. Visfatin cytokine and HMGB-1 protein might act as a good biomarker for diseases.

The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2

Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho β (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation ofKLBin these HCC cells resulted in a fitness defect more severe than that resulting from inactivation ofFGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed thatFGFR3restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.

Aim Overexpression of BCL2L1 (BCL-xL) was associated with platinum resistance in ovarian cancer (OvCa). However, role of copy number (CN) gain of BCL2L1 in OvCa remains elusive. Methods In silico analyses of multiple public datasets were perform. Validation was carried out in our tissue microarray (TMA) of OvCa cases. In vitro and in vivo assays was performed to explore potential targeted compound against BCL2L1-gained OvCa. Results BCL2L1 was gained in ~60% of OvCa. BCL2L1 was differentially expressed between healthy and cancerous ovarian cases. BCL2L1 gain was not prognostic either in overall or in progression-free survival but higher BCL2L1 expression was associated with worsened survival, indicating biological distinction between CN gain and overexpression of the gene. BCL2L1 gain was associated with multi-resistance to various drug with no significant sensitivity to any single agent. Only CRISPR-mediated BCL2L1 knockout, but not shRNA could be inhibitive. Combined genetic silencing of FGFR4/NCAM and BCL2L1 with shRNA induced potent inhibition of BCL2L1-gained OvCa with durable effect. Combined inhibition of FGFR/BCL-xL was required for inhibiting BCL2L1-gained OvCa in vitro and in vivo. Only dual inhibition of FGFR/BCL-xL without platinum was tolerable in vivo. Conclusion Gain of BCL2L1 is associated with resistance to multiple anti-cancer agents in OvCa. Dual inhibition of FGFR4 and BCL-xL showed potent effect and tolerable toxicity, holding promise to further translation.

Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1-/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. 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.

Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC50 value of 4.14 ± 0.96, 2.77 ± 0.082, and 8.10 ± 0.15 nmol/L. It effectively overcomes FGFR1‐V561F/M and other mutantresistance in Ba/F3 stable cells (IC50:8.1–55.0 nM), and effectively inhibits the growth of Ba/F3‐FGFR1‐V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials., FGFR1‐V561F/M mutation is resistant to erdafitinib, pemigatinib, BGJ398, and TAS120 but sensitive to GZD824. GZD824 strongly suppresses FGFR1‐3 and effectively overcomes FGFR1‐V561F, V561M, and other mutant resistance in vitro (IC50:8.1–55.0 nM) and in vivo (TGI=73.4%, 49.8% at 20mg/kg, p.o, q2d). GZD824 as a type II FGFR1 inhibitor overcomes FGFR1‐V561F/M mutant resistance.

Cholesterol gallstone (CGS) disease is characterized by an imbalance in bile acid (BA) metabolism and is closely associated with gut microbiota disorders. However, the role and mechanism by which probiotics targeting the gut microbiota attenuate cholesterol gallstones are still unknown. In this study, Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407 were individually administered to lithogenic-diet (LD)-fed mice for 8 weeks. Both

While fibroblast growth factor receptors (FGFRs) are involved in several biological pathways and FGFR inhibitors may be useful in the treatment of squamous non-small cell lung cancer (Sq-NSCLC), FGFR aberrations are not well characterized in Sq-NSCLC. We comprehensively evaluated FGFR expression, fusions, and variants in 40 fresh-frozen primary Sq-NSCLC (stage IA3–IV) samples and tumor-adjacent normal tissues using real-time PCR and next-generation sequencing (NGS). Protein expression of FGFR1–3 and amplification of FGFR1 were also analyzed. FGFR1 and FGFR4 median gene expression was significantly (p < 0.001) decreased in tumors compared with normal tissue. Increased FGFR3 expression enhanced the recurrence risk (hazard ratio 4.72, p = 0.029), while high FGFR4 expression was associated with lymph node metastasis (p = 0.036). Enhanced FGFR1 gene expression was correlated with FGFR1 protein overexpression (r = 0.75, p = 0.0003), but not with FGFR1 amplification. NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

Immune checkpoint inhibitors (ICIs), which represent the new standard of care for advanced nonsmall cell lung cancer (NCSLC), are not effective in many patients. Biomarkers are needed to guide treatment. Sequencing data of an ICI-treated cohort were analyzed to identify genomic signatures predicting ICI efficacy, followed by validation using multiple independent cohorts. Their predictive mechanism was explored by evaluating the tumor immune microenvironment and tumor mutational burden (TMB). In the discovery cohort, patients carrying FGFR4 alterations (FGFR4

Background Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation. In contrast, intestinal NPC1L1 promotes intestinal cholesterol absorption, increasing biliary cholesterol supersaturation. Ezetimibe (EZE) can inhibit both hepatic and intestinal NPC1L1. However, whether hepatic NPC1L1 can affect CGD progress remains unknown. Methods Mice expressing hepatic NPC1L1 (NPC1L1hepatic-OE mice) were generated using Adeno-associated viruses (AAV) gene delivery. The protein level and function of hepatic NPC1L1 were examined under chow diet, high fat-cholesterol diet (HFCD), and lithogenic diet (LD) feeding. Gallstone formation rates were examined with or without EZE treatment. Fibroblast growth factor 15 (FGF15) treatment and inhibition of fibroblast growth factor receptor 4 (FGFR4) were applied to verify the mechanism of hepatic NPC1L1 degradation. Results The HFCD-fed NPC1L1hepatic-OE mice retained the biliary cholesterol desaturation function of hepatic NPC1L1, whereas EZE treatment decreased biliary cholesterol saturation and did not cause CGD. The ubiquitination and degradation of hepatic NPC1L1 were discovered in LD-fed NPC1L1hepatic-OE mice. Treatment of FGF15 during HFCD feeding and inhibition of FGFR4 during LD feeding could affect the protein level and function of hepatic NPC1L1. Conclusions LD induces the ubiquitination and degradation of hepatic NPC1L1 via the FGF15-FGFR4 pathway. EZE may act as an effective preventative agent for CGD.

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1

Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.Implications:These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

Chronic hepatitis B virus (HBV) infection is one of the major global health problems. Although the small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein, its pathogenic role and molecular mechanism in malignant progression of HBV-related hepatocellular carcinoma (HCC) remain largely unknown. Here we reported that SHBs expression induced epithelial-mesenchymal transition (EMT) process in HCC cells and significantly increased their migratory and invasive ability as well as metastatic potential. Mechanistically, SHBs expression in HCC cells induced endoplasmic reticulum (ER) stress that activated the activating transcription factor 4 (ATF4) to increase the expression and secretion of fibroblast growth factor 19 (FGF19). The autocrine released FGF19 in turn activated JAK2/STAT3 signaling for induction of EMT process in HCC. Notably, SHBs was positively correlated with the expression of mesenchymal markers, the phosphorylation status of JAK2 and STAT3 as well as FGF19 levels in human HCC samples. HCC patients with SHBs positive had a more advanced clinical stage and worse prognosis. These results suggest an important role of SHBs in the metastasis and progression of HCC and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression.

The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03–1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04–1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.

Introduction: High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients. Methods: The prospective Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation study recruited CKD G2–G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD). Results: Carriers of the different alleles did neither differ in baseline LVMI (rs351855: p = 0.861; rs9536314: p = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: p = 0.181; rs9536314: p = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: p = 0.316; rs9536314: p = 0.765) and ASCVD (p = 0.508 and p = 0.800, respectively) did not differ between carriers of different alleles. Discussion/Conclusion: rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.

Background: Nonalcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) and a potential precursor of hepatocellular carcinoma (HCC). In our previous studies, we found that endocrine fibroblast growth factor 21 (FGF21) played a key role in preventing the development of NASH, however, the FGF15/19 mediated-FGFR4 signaling worsened NASH and even contributed to the NASH-HCC transition. The aim of this study is to determine whether FGF15/FGFR4 signaling could alleviate or aggravate NASH in the FGF21KO mice. Methods: NASH models were established in FGF21KO mice fed with high fat methionine-choline deficient (HFMCD) diet to investigate FGF15/FGFR4 signaling during early stage NASH and advanced stage NASH. Human hepatocytes, HepG2 and Hep3B cells, were cultured with human enterocytes Caco-2 cells to mimic gut-liver circulation to investigate the potential mechanism of NASH development. Results: Significant increase of FGF15 production was found in the liver of the NASH-FGF21KO mice, however the increased FGF15 protein was unable to alleviate hepatic lipid accumulation. In contrast, up-regulated FGF15/19/FGFR4 signaling was found in the FGF21KO mice with increased NASH severity, as evident by hepatocyte injury/repair, fibrosis and potential malignant events. In in vitro studies, blockage of FGFR4 by BLU9931 treatment attenuated the lipid accumulation, up-regulated cyclin D1, and epithelial-mesenchymal transition (EMT) in the hepatocytes. Conclusion: The increased FGF15 in NASH-FGF21KO mice could not substitute for FGF21 to compensate its lipid metabolic benefits thereby to prevent NASH development. Up-regulated FGFR4 signaling in NASH-FGF21KO mice coupled to proliferation and EMT events which were widely accepted to be associated with carcinogenic transformation.

Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.

Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe2+ efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.

Background Increasing evidence has indicated that Maelstrom (MAEL) plays an oncogenic role in various human carcinomas. However, the exact function and mechanisms by which MAEL acts in epithelial ovarian cancer (EOC) remain unclear. Results This study demonstrated that MAEL was frequently overexpressed in EOC tissues and cell lines. Overexpression of MAEL was positively correlated with the histological grade of tumors, FIGO stage, and pT/pN/pM status (p p P Conclusion Our findings suggest that overexpression of MAEL plays a crucial oncogenic role in the development and progression of EOC through the upregulation of FGFR4 and subsequent induction of EMT, and also provide new insights on its potential as a therapeutic target for EOC.

Excess fibroblast growth factor (FGF) 23 signaling in patients with chronic kidney disease induces left ventricular hypertrophy. In this issue, Yanucil et al. investigated the interaction of soluble klotho and heparin with FGF23 and FGF receptor isoforms. They concluded that heparin promotes the FGF23-FGF receptor isoform 4 interaction and FGF23 pathogenic effects, supporting an important role of heparin in the pathogenesis of FGF23-mediated left ventricular hypertrophy in chronic kidney disease.

Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended panel of primary surgical specimen-derived and immortalized GBM (stem)cell models and original tumor tissues were screened for FGFR4 expression. GBM models engineered for wild-type and dominant-negative FGFR4 overexpression were investigated regarding aggressiveness and xenograft formation. Gene set enrichment analyses of FGFR4-modulated GBM models were compared to patient-derived datasets. Despite widely absent in adult brain, FGFR4 mRNA was distinctly expressed in embryonic neural stem cells and significantly upregulated in glioblastoma. Pronounced FGFR4 overexpression defined a distinct GBM patient subgroup with dismal prognosis. Expression levels of FGFR4 and its specific ligands FGF19/FGF23 correlated both in vitro and in vivo and were progressively upregulated in the vast majority of recurrent tumors. Based on overexpression/blockade experiments in respective GBM models, a central pro-oncogenic function of FGFR4 concerning viability, adhesion, migration, and clonogenicity was identified. Expression of dominant-negative FGFR4 resulted in diminished (subcutaneous) or blocked (orthotopic) GBM xenograft formation in the mouse and reduced invasiveness in zebrafish xenotransplantation models. In vitro and in vivo data consistently revealed distinct FGFR4 and integrin/extracellular matrix interactions. Accordingly, FGFR4 blockade profoundly sensitized FGFR4-overexpressing GBM models towards integrin/focal adhesion kinase inhibitors. Collectively, FGFR4 overexpression contributes to the malignant phenotype of a highly aggressive GBM subgroup and is associated with integrin-related therapeutic vulnerabilities.

Background Highly differentiated follicular carcinoma (HDFCO) is a rare form of struma-derived thyroid-type carcinoma in ovary, defined as ovarian struma spreading beyond ovary but consisting of benign thyroid tissues. No more than 30 cases of HDFCO have been reported since it was first recognized in 2008. The clinicopathologic and molecular features of HDFCO remain unclear up till now. Case presentation A 38-year-old, para 1 gravida 5 woman has a long history of recurrent right ovarian cysts. Histological evaluation showed the tumor progressed from ovarian mature cystic teratoma (OMCT) to highly differentiated follicular carcinoma (HDFCO) during three relapses. Whole-exome sequencing revealed the germline FGFR4 Gly388Arg polymorphism. Repeated operations were performed to remove lesions for the first two relapses. On the third recurrence, the patient received radical surgery with subsequent thyroidectomy and radioactive iodine ablation. No evidence of disease was observed by February 2022 (8 months). Conclusions The germline FGFR4 Gly388Arg polymorphism may accelerate the malignant transformation of HDFCO, probably by working as a second hit in the developing spectrum.

Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1–4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1–4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3–50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1–4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing.Significance:Preclinical characterization of futibatinib, an irreversible FGFR1–4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors.

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., Liver cancer: combining two drugs for improved therapeutic effect The drugs FGF401 and vinorelbine, when working together synergistically, could be effective in treating those liver cancers driven by the activity of the fibroblast growth factor 19 (FGF19) protein. The drugs’ effects on human tumors grafted into mice were studied by an international research team led by Hung Huynh at the National Cancer Centre in Singapore. FGF401 is a small molecule that inhibits the activity of the receptor protein that the FGF19 growth factor interacts with to promote some cancers. Vinorelbine disrupts protein microtubules required for the cell division that allows cancer cells to multiply. In combination, the drugs achieved significantly enhanced anti-cancer effects which can now be tested in clinical trials. The research also uncovered new details of FGF401’s therapeutic actions, including its ability to restore healthy blood vessel formation.

This study demonstrates overexpression of TRIP13 in colorectal cancers is independent of patient's gender, age, race/ethnicity, pathologic stage (primary and liver metastatic lesions), and p53 and microsatellite instability status. Furthermore, it establishes role of TRIP13 in colorectal cancer metastasis and identifies COL6A3, TREM2, SHC3, and KLK7 as its downstream targets. Additionally, TRIP13 activates EGFR‐AKT pathway via its interaction with FGFR4., Overexpression of TRIP13, a member of the AAA‐ATPase family, is linked with various cancers, but its role in metastasis is unknown in colorectal cancer (CRC). In the current study, we investigated the role TRIP13 in experimental metastasis and its involvement in regulation of WNT/β‐catenin and EGFR signaling pathways. Evaluation of formalin‐fixed paraffin‐embedded (FFPE) and frozen tissues of adenomas and CRCs, along with their corresponding normal samples, showed that TRIP13 was gradually increased in its phenotypic expression from adenoma to carcinoma and that its overexpression in CRCs was independent of patient's gender, age, race/ethnicity, pathologic stage, and p53 and microsatellite instability (MSI) status. Moreover, liver metastases of CRCs showed TRIP13 overexpression as compared to matched adjacent liver tissues, indicating the biological relevance of TRIP13 in CRC progression and metastasis. TRIP13 knockdown impeded colony formation, invasion, motility, and spheroid‐forming capacity of CRC cells irrespective of their p53 and MSI status. Furthermore, xenograft studies demonstrated high expression of TRIP13 contributed to tumor growth and metastasis. Depletion of TRIP13 in CRC cells decreased metastasis and it was independent of the p53 and MSI status. Furthermore, TRIP13 interacted with a tyrosine kinase, FGFR4; this interaction could be essential for activation of the EGFR‐AKT pathway. In addition, we demonstrated the involvement of TRIP13 in the Wnt signaling pathway and in the epithelial–mesenchymal transition. Cell‐based assays revealed that miR‐192 and PNPT1 regulate TRIP13 expression in CRC. Additionally, RNA sequencing of CRC cells with TRIP13 knockdown identified COL6A3, TREM2, SHC3, and KLK7 as downstream targets that may have functional relevance in TRIP13‐mediated tumor growth and metastasis. In summary, our results demonstrated that TRIP13 promotes tumor growth and metastasis regardless of p53 and MSI status, and indicated that it is a target for therapy of CRC.

FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2(–)). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER(+) tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer., Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.

In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1–4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1–3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1–3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.

Purpose Fibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets. Materials and methods FGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines. Results Among 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele. Conclusion The exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.

HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.

Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1–not estimable [NE]), and 4.6 (95% CI 1.1–NE) months, respectively (p = 0.003). Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.

Background Malignant pilomatricoma (MP) is a rare cancer of the hair matrix with only a few cases reported in literature. Given the rarity of this cancer and the lack of relevant genetic data, very little is known about the nature of the molecular pathophysiology except the involvement of the Catenin Beta 1 (CTNNB1)/Wnt/β-catenin signaling pathway in some cases. Materials and methods We describe the whole-exome genomic profiling of four samples from two patients: 1) an MP from patient I, 2) a coexisting benign pilomatricoma (BP) from patient I, 3) a BP from an age and location-matched control patient II, and 4) normal skin tissue from patient II. Results We detected a pathogenic somatic missense mutation in fibroblast growth factor receptor 4 (FGFR4) (c.1162G>A, p. Gly388Arg) in MP and coexisting BP in patient I, whereas the control BP harbored the classical CTNNB1 mutant. Conclusion This study, the first comparative analysis of benign and MP through whole-exome analysis, identified a novel oncogenic mutation in FGFR4.

There is controversy regarding whether excess FGF23 causes left ventricular hypertrophy (LVH) directly through activation of fibroblast growth factor receptor 4 (FGFR4) in cardiomyocytes or indirectly through reductions in soluble Klotho (sK). We investigated the respective roles of myocardial FGFR4 and sKL in mediating FGF23-induced LVH using mouse genetic and pharmacological approaches. To investigate a direct role of myocardial FGFR4 in mediating the cardiotoxic effects of excess circulating FGF23, we administered rFGF23 to mice with cardiac-specific loss of FGFR4 (FGFR4 heart-cKO). We tested a model of sKL deficiency, hypertension and LVH created by the conditional deletion of FGFR1 in the renal distal tubule (FGFR1DT cKO mice). The cardioprotective effects of sKL in both mouse models was assessed by the systemic administration of recombinant sKL. We confirmed that FGF23 treatment activates PLCγ in the heart and induces LVH in the absence of membrane α-Klotho. Conditional deletion of FGFR4 in the myocardium prevented rFGF23-induced LVH in mice, establishing direct cardiotoxicity of FGF23 through activation of FGFR4. Recombinant sKL administration prevented LVH, but not HTN, in FGFR1DT cKO mice, consistent with direct cardioprotective effects. Co-administration of recombinant sKL with FGF23 in culture inhibited rFGF23-induced p-PLCγ signaling. Thus, FGF23 ability to include LVH represents a balance between FGF23 direct cardiac activation of FGFR4 and the modulating effects of circulating sKL to alter FGF23-dependent myocardial signaling pathways.

The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.