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ABSTRACTTyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

BACKGROUND: Preliminary research by our group suggests that targeting fibroblast growth factor receptor 1 (FGFR1) may be an effective strategy for treating RA. OBJECTIVE: To investigate the effects of an FGFR1 inhibitor (PD173074) on bone destruction in rats with collagen-induced arthritis. METHODS: Twenty-five female Sprague-Dawley rats were randomly divided into five groups: normal control group, model group, methotrexate group, low- dose PD173074 group, and high-dose PD173074 group. Except for the normal control group, rat models of type II collagen-induced arthritis were made in each group. After successful modeling, rats were injected intraperitoneally with sterile PBS in the normal and model groups, 1.04 mg/kg methotrexate in the methotrexate group, and 5 and 20 mg/kg in the low-dose group and high-dose PD173074 groups, once a week. After 4 weeks of drug administration, clinical symptoms and joint swelling in rats were observed. Micro-CT was used for three-dimensional reconstruction and analysis of the ankle joints. Pathological changes in the ankle joints were observed. Periarticular angiogenesis and the expression of receptor activator of nuclear factor-κB ligand were detected. The expression levels of p-FGFR1, vascular endothelial growth factor A, and tartrate-resistant acid phosphatase in the synovial membrane were measured. Pathological changes in the liver, spleen, and kidney were observed and liver, spleen, and kidney indices were calculated. RESULTS AND CONCLUSION: PD173074 could alleviate clinical symptoms and joint swelling, delay bone loss, improve bone structure, reduce synovial invasion and cartilage bone erosion, reduce the number of periarticular osteoclasts, inhibit angiogenesis in synovial tissues, reduce the expression of receptor activator of nuclear factor-κB ligand, and inhibit the expression of FGFR1 phosphorylated protein, tartrate-resistant acid phosphatase and vascular endothelial growth factor A. Pathologic observation of the liver, spleen and kidney in rats showed no obvious toxic side effects after PD173074 treatment. To conclude, the FGFR1 inhibitor can delay the progression of joint inflammation and bone destruction and inhibit angiogenesis in the rat model of type II collagen-induced arthritis. The therapeutic effect of PD173074 has been preliminarily validated in the type II collagen-induced arthritis model and may act by inhibiting FGFR1 phosphorylation, which provides a direction for the search of new therapeutic targets for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background: Comprehensive molecular assessment of cancers could open up new horizons for novel therapies. Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been previously demonstrated in non-small cell lung cancer (NSCLC) patients. The current study aimed to evaluate the prevalence of FGFR1 gene amplification and its association with clinical and demographic data in a group of NSCLC patients. Methods: The present study was performed on eighty-eight NSCLC patients who underwent bronchoscopy or surgery in Qaem Hospital, Mashhad, between 2010 and 2016. FGFR1 gene amplification was detected using real-time PCR assay on DNA extracted from paraffin-embedded tissue blocks of patients. Also, patients' clinical and demographic data, such as their survival, were evaluated. Statistical analysis was carried out using SPSS software. Results: Seventeen (19.31%) out of eighty-eight patients with NSCLC presented FGFR1 gene amplification. Besides, we found a significant association between FGFR1 amplification and cigarette smoking (p-value= 0.01; OR: 4.08). Although cases with squamous cell carcinoma (SCC) showed a higher prevalence of FGFR1 amplification compared to adenocarcinoma patients, the difference was not statistically significant (pvalue> 0.05). In addition, our findings showed no relationship between FGFR1 gene amplification and other clinical and demographic factors, including age, sex, grade, tumor operability, and survival. Conclusion: The frequency of FGFR1 amplification is estimated at 20% in the current study (26% in SCC versus 11% in adenocarcinoma; p-value= 0.07). Moreover, we found a direct association between FGFR1 amplification and cigarette smoking. However, no significant relationship with survival or other factors was observed. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors. Materials and methods: Lung cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and in vivo, mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established. Results: The antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm3 and 2174 mm3 in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses. Conclusions: Our preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this interaction.

Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human body, and around 85% of phosphate is present in bone as a constituent of hydroxyapatite, Ca10(PO4)6(OH)2. Because hypophosphatemia induces rickets/osteomalacia, and hyperphosphatemia results in ectopic calcification, blood phosphate (inorganic form) level must be regulated in a narrow range (2.5 mg/dL to 4.5 me/dL in adults). However, as yet it is unknown how bone senses changes in blood phosphate level, and how bone regulates the production of FGF23. Our previous data indicated that high extracellular phosphate phosphorylates FGF receptor 1 (FGFR1) in an unliganded manner, and its downstream intracellular signaling pathway regulates the expression of GALNT3. Furthermore, the post-translational modification of FGF23 protein via a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production due to high dietary phosphate. Therefore, our research group proposes that FGFR1 works as a phosphate-sensing receptor at least in the regulation of FGF23 production and blood phosphate level, and phosphate behaves as a first messenger. Phosphate is involved in various effects, such as stimulation of parathyroid hormone (PTH) synthesis, vascular calcification, and renal dysfunction. Several of these responses to phosphate are considered as phosphate toxicity. However, it is not clear whether FGFR1 is involved in these responses to phosphate. The elucidation of phosphate-sensing mechanisms may lead to the identification of treatment strategies for patients with abnormal phosphate metabolism.

Objectives RA is an autoimmune disease characterized by destructive polyarthritis. CD4+ T cells are pivotal to its pathogenesis, and our previous study revealed the expression of fibroblast growth factor receptor 1 (FGFR1) is modulated by MTX treatment in CD4+ T cells of RA patients; however, the roles of FGFR1 in CD4+ T cells in the pathogenesis of RA is unclear. Therefore, in this study, we aimed to characterize FGFR1-positive CD4+ T cells in RA patients. Methods The abundance of FGFR1-positive CD4+ T cells in peripheral blood and synovium was determined. Single-cell RNA sequencing (scRNA-seq) was performed on synovial CD4+ T cells to characterize FGFR1-positive cells. In addition, T cell activation status and cytokine production were determined using flow cytometry. Results The percentage of FGFR1-positive CD4+ T cells in the peripheral blood was higher in RA patients than in healthy controls (P  =0.0035). They were also present in the synovium of active RA patients. The results of scRNA-seq revealed that peripheral Th (Tph) cells preferentially expressed FGFR1. Additionally, these FGFR1-positive Tph cells displayed a terminal effector cell phenotype. Consistent with this finding, FGFR1-positive CD4+ T cells in peripheral blood expressed IL-21 and IFN-γ. Conclusion Our study provides evidence that FGFR1 marks terminal effector Tph cells in patients with RA. [ABSTRACT FROM AUTHOR]

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Purpose: Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model. Methods: Twenty-four male Sprague–Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations. Results: All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05). Conclusions: Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model. [ABSTRACT FROM AUTHOR]

Isolated deficiency of gonadotropin-releasing hormone is a heterogeneous disorder with wide genetic and clinical overlap. It mainly presents as hypogonadotropic hypogonadism (HH). HH associated with anosmia is known as Kallmann syndrome (KS), while its normosmic variant is called normosmic idiopathic HH. However, it is associated with several nonreproductive features including dental defects. Fibroblast growth factor receptor 1 gene mutation, which is seen in the autosomal dominant form of idiopathic HH (HH 2), has often been linked to the associated dental abnormalities and orofacial defects; however, no literature exists for its association with anosmin-1 (ANOS1) gene mutation which is found in the X-linked form of HH (KS). ANOS1 gene was earlier known as KAL1 (Kallmann syndrome 1) gene, and encodes for the extracellular matrix protein called anosmin. Hence, we report a case of idiopathic HH (KS) so as to delineate the possible role of ANOS1 gene in dental/orofacial development. This can help prioritize gene screening and also provide scope for further genetic studies required to prove such association.

Introduction Osteoarthritis (OA) is a joint condition that causes significant impairment of the chondrocyte. The gradual degradation of the cartilage lining of one or more freely moving joints, as well as persistent inflammation, are the causes of osteoarthritis. Current medication focuses on alleviating symptoms rather than curing the condition. Methods This review article was completed by searching for information with the keywords “Fibroblast Growth Factor Receptor-1”, “Extracellular Vesicle”, and “Osteoarthritis” in various journals in several search engines. Out of 102 publications found, 95 were suitable to be studied. Results The upregulated amount of fibroblast growth factor receptors (FGFR1) signaling suggesting the progression of degenerative cartilage that commonly seen in osteoarthritis (OA) patients. Several studies showed that the involvement of extracellular vesicles (EV) derived from MSCs could enhance cartilage repair and protect the cartilage from degradation. EVs have the potential to deliver effects to specific cell types through ligand-receptor interactions and several pathway mechanisms related with the FGFR1. EVs and FGFR1 have been postulated in recent years as possible therapeutic targets in human articular cartilage. Conclusions The protective benefits on both chondrocytes and synoviocytes in OA patients can be achieved by administering the MSC-EVs that may also stimulate chondrocyte proliferation and migration. EVs have a promising potential to become a novel therapy for treating patients with OA. However, further research is needed to discover possible application of this therapy.

Isolated deficiency of gonadotropin-releasing hormone is a heterogeneous disorder with wide genetic and clinical overlap. It mainly presents as hypogonadotropic hypogonadism (HH). HH associated with anosmia is known as Kallmann syndrome (KS), while its normosmic variant is called normosmic idiopathic HH. However, it is associated with several nonreproductive features including dental defects. Fibroblast growth factor receptor 1 gene mutation, which is seen in the autosomal dominant form of idiopathic HH (HH 2), has often been linked to the associated dental abnormalities and orofacial defects; however, no literature exists for its association with anosmin-1 (ANOS1) gene mutation which is found in the X-linked form of HH (KS). ANOS1 gene was earlier known as KAL1 (Kallmann syndrome 1) gene, and encodes for the extracellular matrix protein called anosmin. Hence, we report a case of idiopathic HH (KS) so as to delineate the possible role of ANOS1 gene in dental/orofacial development. This can help prioritize gene screening and also provide scope for further genetic studies required to prove such association. [ABSTRACT FROM AUTHOR]

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH. [ABSTRACT FROM AUTHOR]

Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is a rare disorder with pubertal delay, normal sense of smell. nIHH with a fibroblast growth factor receptor 1 mutation is much more common in adult males but is rarely reported in females. In addition, the assessment and monitoring of ovarian function in nIHH females has often been ignored. We report a 24-year-old nIHH female with the complaint of primary amenorrhea and delayed secondary sexual traits development. Whole-Exome Sequencing analysis revealed a novel mutation in the third exon of fibroblast growth factor receptor 1 gene (c.289 G > A), which resulted in the replacement of glycine acid with serine. Then the patient was recommended to start with the hormone therapy (HT). After several months of estrogen combined with progesterone replacement, the patient had regular menstruation. The breast development and genital development gradually became Tanner stage 5. Anti-Müllerian hormones (AMHs) were also evaluated and the serum AMH level keeps fluctuating within the normal reference range. We highlight the great variability of fibroblast growth factor receptor 1 mutation phenotypes and the evaluation of ovarian reserve in nIHH, and the hormone replacement therapy is necessary to improve secondary sexual development for patients with nIHH. [ABSTRACT FROM AUTHOR]

Introduction Identifying target oncogenic alterations in lung cancer represents a major development in disease management. We examined the association of fibroblast growth factor receptor 1 (FGFR1) gene amplification with pathological characteristics and geographic region. Material and methods We conducted a meta-analysis of studies published between January 2010 and October 2016. Relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated regarding the rate of FGFR1 amplification in different lung cancer types and geographic region. Results Twenty-three studies (5252 patients) were included. There was heterogeneity between studies. However, in subgroup analyses for squamous cell carcinoma (SCC), small cell lung cancer (SCLC), studies using the same definition of FGFR1 amplification, and those from Australia, no significant heterogeneity was detected. The prevalence of FGFR1 amplification in these studies ranged from 4.9% to 49.2% in non-small cell lung cancer (NSCLC), 5.1% to 41.5% in SCC, 0% to 14.7% in adenocarcinoma, and 0% to 7.8% in SCLC. The prevalence of FGFR1 amplification was significantly higher in SCC than in adenocarcinoma (RR = 5.2) and SCLC (RR = 4.2). The prevalence of FGFR1 amplification ranged from 5.6% to 22.2% in Europe, 4.1% to 18.2% in the United States, 7.8% to 49.2% in Asia, and 14.2% to 18.6% in Australia. The rate of FGFR1 amplification was higher in Asians than in non-Asians (RR = 1.9) in NSCLC. Conclusions These results suggest that FGFR1 amplification occurs more frequently in SCC and in Asians. FGFR1 amplification may be a potential new therapeutic target for specific patients and lung cancer subtypes.

Background: Fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors., Materials and Methods: Lung cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and  in vivo , mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established., Results: The antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm 3 and 2174 mm 3 in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro , the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo , pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses., Conclusions: Our preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this interaction., (© 2024 The Author(s).)

Myeloid/lymphoid neoplasm with BCR-FGFR1 is a rare diagnosis with few reported cases. Myeloid/lymphoid neoplasm with a BCR-FGFR1 has an atypical CML phenotype. BCR-FGFR1 is not associated with eosinophilia or lymphoblastic lymphoma, unlike other FGFR1 rearrangements. Myeloid/lymphoid neoplasm with a BCR-FGFR1 has an aggressive course with rapid evolution to acute myeloid leukemia. Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/ BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1- partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/ BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity. [ABSTRACT FROM AUTHOR]

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS‐driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo‐like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS‐mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti‐proliferative effects and cell death in KRAS‐mutant lung and pancreatic but not colon nor KRAS wild‐type cancer cells. Mechanistically, co‐targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress‐activated c‐Jun N‐terminal kinase (JNK)/p38 pathway and E2F1‐induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS‐mutant patient‐derived xenografts and a genetically engineered mouse model of Kras‐induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS‐mutant cancer. SYNOPSIS: Human cancers driven by oncogenic KRAS mutations are common and among the most difficult‐to‐treat tumors. This study reports a synergistic drug combination by targeting FGFR1 and PLK1 and identifies autophagy as a protective mechanism that limits the efficacy of FGFR1/PLK1 inhibitor therapy in KRAS‐mutant lung cancer, suggesting a novel strategy to treat the daunting disease. FGFR‐ and PLK1‐targeted agents synergize in inhibiting KRAS‐mutant lung and pancreatic cancer cells.FGFR/PLK1 inhibitor therapy targets a metabolic liability by abrogating ROS homeostasis in KRAS‐mutant cancer cells.Autophagy protects against FGFR/PLK1 inhibitor‐induced cytotoxicity.Combined inhibition of FGFR, PLK1, and autophagy shows potent anti‐tumor efficacy in mouse models of KRAS‐mutant lung cancer. [ABSTRACT FROM AUTHOR]

Abstract KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS‐driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo‐like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS‐mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti‐proliferative effects and cell death in KRAS‐mutant lung and pancreatic but not colon nor KRAS wild‐type cancer cells. Mechanistically, co‐targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress‐activated c‐Jun N‐terminal kinase (JNK)/p38 pathway and E2F1‐induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS‐mutant patient‐derived xenografts and a genetically engineered mouse model of Kras‐induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS‐mutant cancer.

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.

Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely. Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations. Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity. FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse. [ABSTRACT FROM AUTHOR]

After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including "ectopic FGF23 syndrome," "alcohol consumption-induced FGF23-related hypophosphatemia," "anti-mitochondrial antibody associated hypophosphatemia," and "vitamin D-dependent rickets type 3." Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced. [ABSTRACT FROM AUTHOR]

Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1‐dependent downstream signaling and FGFR1 ligand binding. To date, the major group of drugs being developed for treatment of FGFR1‐dependent cancers are small‐molecule tyrosine kinase inhibitors; however, the limited specificity of these drugs has led to increasing attempts to design molecules targeting the extracellular domain of FGFR1. Here, we used the phage display technique to select cyclic peptides F8 (ACSLNHTVNC) and G10 (ACSAKTTSAC) as binders of the fibroblast growth factor 1 (FGF1)–FGFR1 interface. ELISA and in vitro cell assays were performed to reveal that cyclic peptide F8 is more effective in preventing the FGF1–FGFR1 interaction, and also decreases FGF1‐induced proliferation of BA/F3 FGFR1c cells by over 40%. Such an effect was not observed for BA/F3 cells lacking FGFR1. Therefore, cyclic peptide F8 can act as a FGF1–FGFR1 interaction antagonist, and may be suitable for further development for potential use in therapies against FGFR1‐expressing cancer cells.

Abstract Background Osteosarcoma (OS) is the most common bone malignancy prevalent in children and young adults. MicroRNA-133b (miR-133b), through directly targeting the fibroblast growth factor receptor 1 (FGFR1), is increasingly recognized as a tumor suppressor in different types of cancers. However, little is known on the biological and functional significance of miR-133b/FGFR1 regulation in osteosarcoma. Methods The expressions of miR-133b and FGFR1 were examined by RT-qPCR and compared between 30 paired normal bone tissues and OS tissues, and also between normal osteoblasts and three OS cells lines, MG-63, U2OS, and SAOS-2. Using U2OS and MG-63 as the model system, the functional significance of miR-133b and FGFR1 was assessed on cell viability, proliferation, apoptosis, migration/invasion, and epithelial–mesenchymal transition (EMT) by overexpressing miR-133b and down-regulating FGFR1 expression, respectively. Furthermore, the signaling cascades controlled by miR-133b/FGFR1 were examined. Results miR-133b was significantly down-regulated while FGFR1 robustly up-regulated in OS tissues and OS cell lines, when compared to normal bone tissues and normal osteoblasts, respectively. Low miR-133b expression and high FGFR1 expression were associated with location of the malignant lesion, advanced clinical stage, and distant metastasis. FGFR1 was a direct target of miR-133b. Overexpressing miRNA-133b or knocking down FGFR1 significantly reduced the viability, proliferation, migration/invasion, and EMT, but promoted apoptosis of both MG-63 and U2OS cells. Both the Ras/MAPK and PI3K/Akt intracellular signaling cascades were inhibited in response to overexpressing miRNA-133b or knocking down FGFR1 in OS cells. Conclusion miR-133b, by targeting FGFR1, presents a plethora of tumor suppressor activities in OS cells. Boosting miR-133b expression or reducing FGFR1 expression may benefit OS therapy.

In humans and mice, inactivating mutations in fibroblast growth factor receptor 1 (Fgfr1) lead to gonadotropin-releasing hormone (GnRH) deficiency and a host of downstream reproductive disorders. It was unclear if Fgfr1 signaling directly upon GnRH neurons critically drove the establishment of a functional GnRH system. To answer this question, we generated a mouse model with a conditional deletion of Fgfr1 in GnRH neurons using the Cre/loxP approach. These mice, called Fgfr1cKO mice, were examined along with control mice for their pubertal onset and a host of reproductive axis functions. Our results showed that Fgfr1cKO mice harbored no detectable defects in the GnRH system and pubertal onset, suffered only subtle changes in the pituitary function, but exhibited significantly disrupted testicular and ovarian morphology at 25 days of age, indicating impaired gametogenesis at a young age. However, these disruptions were transient and became undetectable in older mice. Our results suggest that Fgfr1 signaling directly on GnRH neurons supports, to some extent, the reproductive axis function in the period leading to the early phase of puberty, but is not critically required for pubertal onset or reproductive maintenance in sexually mature animals.

Abstract AZD9291 can effectively prolong survival of non‐small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH‐sensitive shell–core nanoparticles CP@NP‐cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP‐cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP‐cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH‐sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP‐cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p‐ERK1/2 in vitro. CQ in CP@NP‐cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP‐cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.

In humans and mice, inactivating mutations in fibroblast growth factor receptor 1 (Fgfr1) lead to gonadotropin-releasing hormone (GnRH) deficiency and a host of downstream reproductive disorders. It was unclear if Fgfr1 signaling directly upon GnRH neurons critically drove the establishment of a functional GnRH system. To answer this question, we generated a mouse model with a conditional deletion of Fgfr1 in GnRH neurons using the Cre/loxP approach. These mice, called Fgfr1cKO mice, were examined along with control mice for their pubertal onset and a host of reproductive axis functions. Our results showed that Fgfr1cKO mice harbored no detectable defects in the GnRH system and pubertal onset, suffered only subtle changes in the pituitary function, but exhibited significantly disrupted testicular and ovarian morphology at 25 days of age, indicating impaired gametogenesis at a young age. However, these disruptions were transient and became undetectable in older mice. Our results suggest that Fgfr1 signaling directly on GnRH neurons supports, to some extent, the reproductive axis function in the period leading to the early phase of puberty, but is not critically required for pubertal onset or reproductive maintenance in sexually mature animals. [ABSTRACT FROM AUTHOR]

AZD9291 can effectively prolong survival of non‐small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH‐sensitive shell–core nanoparticles CP@NP‐cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP‐cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP‐cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH‐sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP‐cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p‐ERK1/2 in vitro. CQ in CP@NP‐cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP‐cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 ( HSPA5 ) and fibroblast growth factor receptor 1 ( FGFR1 ). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human body, and around 85% of phosphate is present in bone as a constituent of hydroxyapatite, Ca 10 (PO 4 ) 6 (OH) 2 . Because hypophosphatemia induces rickets/osteomalacia, and hyperphosphatemia results in ectopic calcification, blood phosphate (inorganic form) level must be regulated in a narrow range (2.5 mg/dL to 4.5 me/dL in adults). However, as yet it is unknown how bone senses changes in blood phosphate level, and how bone regulates the production of FGF23. Our previous data indicated that high extracellular phosphate phosphorylates FGF receptor 1 (FGFR1) in an unliganded manner, and its downstream intracellular signaling pathway regulates the expression of GALNT3. Furthermore, the post-translational modification of FGF23 protein via a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production due to high dietary phosphate. Therefore, our research group proposes that FGFR1 works as a phosphate-sensing receptor at least in the regulation of FGF23 production and blood phosphate level, and phosphate behaves as a first messenger. Phosphate is involved in various effects, such as stimulation of parathyroid hormone (PTH) synthesis, vascular calcification, and renal dysfunction. Several of these responses to phosphate are considered as phosphate toxicity. However, it is not clear whether FGFR1 is involved in these responses to phosphate. The elucidation of phosphate-sensing mechanisms may lead to the identification of treatment strategies for patients with abnormal phosphate metabolism.

The discovery of novel therapeutic agents with potent anticancer activity remains a critical challenge in drug development. Natural products, particularly bioactive phytoconstituents derived from plants, have emerged as promising sources for anticancer drug discovery. In this study, we used virtual screening techniques to explore the potential of bioactive phytoconstituents as inhibitors of fibroblast growth factor receptor 1 (FGFR1), a key signaling protein implicated in cancer progression. We used virtual screening techniques to analyze phytoconstituents extracted from the IMPPAT 2.0 database. Our primary objective was to discover promising inhibitors of FGFR1. To ensure the selection of promising candidates, we initially filtered the molecules based on their physicochemical properties. Subsequently, we performed binding affinity calculations, PAINS, ADMET, and PASS filters to identify nontoxic and highly effective hits. Through this screening process, one phytocompound, namely Mundulone, emerged as a potential lead. This compound demonstrated an appreciable affinity for FGFR1 and exhibited specific interactions with the ATP-binding site residues. To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics. These analyses provided valuable information regarding the dynamic behavior and stability of the compounds in complexes with FGFR1. Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field.Communicated by Ramaswamy H. Sarma.

Background and objective The methods of detection for recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) have hysteresis and one-sidedness. This study summarizes the relationship between the circulating tumor cell (CTC) in peripheral blood, expression of fibroblast growth factor receptor 1 (FGFR1) and clinic pathological features in 30 patients with NSCLC so as to provide new ideas for the detection of tumor recurrence and metastasis. Methods To analyze the clinical data and CTC detection data of 30 cases of NSCLC in Department of Thoracic Surgery, Peking Union Medical College Hospital from November 2016 to June 2017. Results Data analysis showed that the positive rate of CTC in peripheral blood was remarkably correlated with the smoking history (P=0.016). There was no significant correlation among the pathological type and CTC positive rate and the expression of FGFR1 (P=0.202, P=0.806). There was no significant difference in the expression of FGFR1 in different type CTC cells (P=0.094). Conclusion The positive rate of CTC was significantly correlated with the smoking history of patients with NSCLC. There was no significant difference in CTC classification and FGFR1 expression in different pathological types of NSCLC. There was no significant difference in the expression of FGFR1 between different types of CTCs. We look forward to a larger sample size and inclusion of follow-up data to arrive at more clinically relevant conclusions about CTC and FGFR1 gene expression.

Aims: This study aimed to investigate the clinicopathological significance of FGFR1 and c‐MYC expression, particularly in relation to angiogenesis in clear cell renal cell carcinoma (CCRCC). Methods and results: Immunohistochemistry and fluorescence in‐situ hybridisation were conducted with tissue microarrays from 91 metastatic CCRCC patients who received VEGF receptor tyrosine kinase inhibitors (VEGFR‐TKIs). The expression of angiogenic molecules, FGFR1 and c‐MYC, and tumoral vascular density (TVD) and mRNA expression and TVD of 533 CCRCCs in The Cancer Genome Atlas (TCGA) were analysed. FGFR1, pFGFR1 and c‐MYC expression was observed in 29.1, 74.4 and 30.8% of tumours, respectively. FGFR1high was an independent worse prognostic factor for overall (HR = 1.871, P = 0.032) and progression‐free (HR = 1.976, P = 0.016) survival. FGFR1high was significantly related to VEGFR‐TKI responsiveness (P = 0.011). The presence of FGFR1high/c‐MYChigh showed a positive correlation with proangiogenic markers, including VEGF (P = 0.018) and HIF‐1α (P < 0.0001). FGFR1high/c‐MYChigh tumours showed higher TVDs together with higher VEGFR2 and PDGFR‐β expression (both P < 0.0001). FGFR1 and c‐MYC expression was also positively correlated with the expression of hypoxia‐related and proangiogenic‐related genes in the TCGA data. Conclusions: FGFR1 and c‐MYC may be involved in tumour angiogenesis and FGFR1 may represent a promising therapeutic target in metastatic CCRCC. [ABSTRACT FROM AUTHOR]

In age‐related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1. In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD. [ABSTRACT FROM AUTHOR]

The leukaemic cells are genetically characterized by the fusion of the I FGFR1 i gene to different 5' partner genes, resulting in constitutive activation of the kinase domain within FGFR1. We performed fluorescence I in situ i hybridization analysis using a FGFR1 break apart probe (Abbott Molecular, Des Plaines, IL, USA) and detected 90% of positive cells (Fig B).: Conventional R-banding analysis showed 46,XY,t(3;8)(q12;p11),del(9)(q21q33)[10] (Fig C). (D) RNA sequencing analysis results revealed one breakpoint in exon 8 of the TFG gene and one breakpoint in exon 10 of the FGFR1 gene. We expressed empty vector or HA-tagged TFG-FGFR1 in 293T cells, and investigated some downstream FGFR1 targets, such as MYC in cell proliferation, STAT3 and phosphorylated STAT3 in cell signal transduction. [Extracted from the article]

Purpose The purpose of this study was to reveal the clinicopathological characteristics and prognostic implications associated with fibroblast growth factor receptor 1 (FGFR1) amplification in colorectal cancers (CRCs). Materials and Methods We measured the copy number of FGFR1 by droplet digital polymerase chain reaction (ddPCR), and analyzed the FGFR1 expression by immunohistochemistry, in 764 surgically resected CRCs (SNUH2007 dataset, 384 CRCs; SNUH Folfox dataset, 380 CRCs). Results CRCs with > 3.3 copies of the FGFR1 gene were classified as FGFR1 amplified. FGFR1 amplification was found in 10 of the 384 CRCs (2.6%) in the SNUH2007 dataset, and in 28 of the 380 CRCs (7.4%) in the SNUH Folfox dataset. In the SNUH2007 dataset, there was no association between the FGFR1 copy number status and sex, gross appearance, stage, or differentiation. High FGFR1 expression was associated with female sex and KRAS mutation. At the molecular level, FGFR1 amplification was mutually exclusive with BRAF mutation, microsatellite instability, and MLH1 methylation, in both SNUH2007 and SNUH Folfox datasets. Survival analysis revealed that FGFR1 amplification was associated with significantly worse clinical outcome compared with no FGFR1 amplification, in both SNUH2007 and SNUH Folfox datasets. Within the SNUH2007 dataset, CRC patients with high FGFR1 expression had an inferior progression-free survival compared with those with low FGFR1 expression. The FGFR inhibitor, PD173074, repressed the proliferation of a CRC cell line overexpressing FGFR1, but not of cells with FGFR1 amplification. Conclusion FGFR1 amplification measured by ddPCR can be a prognostic indicator of poor clinical outcome in patients with CRCs. [ABSTRACT FROM AUTHOR]

Introduction: Identifying target oncogenic alterations in lung cancer represents a major development in disease management. We examined the association of fibroblast growth factor receptor 1 (FGFR1) gene amplification with pathological characteristics and geographic region.Material and Methods: We conducted a meta-analysis of studies published between January 2010 and October 2016. Relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated regarding the rate of FGFR1 amplification in different lung cancer types and geographic region.Results: Twenty-three studies (5252 patients) were included. There was heterogeneity between studies. However, in subgroup analyses for squamous cell carcinoma (SCC), small cell lung cancer (SCLC), studies using the same definition of FGFR1 amplification, and those from Australia, no significant heterogeneity was detected. The prevalence of FGFR1 amplification in these studies ranged from 4.9% to 49.2% in non-small cell lung cancer (NSCLC), 5.1% to 41.5% in SCC, 0% to 14.7% in adenocarcinoma, and 0% to 7.8% in SCLC. The prevalence of FGFR1 amplification was significantly higher in SCC than in adenocarcinoma (RR = 5.2) and SCLC (RR = 4.2). The prevalence of FGFR1 amplification ranged from 5.6% to 22.2% in Europe, 4.1% to 18.2% in the United States, 7.8% to 49.2% in Asia, and 14.2% to 18.6% in Australia. The rate of FGFR1 amplification was higher in Asians than in non-Asians (RR = 1.9) in NSCLC.Conclusions: These results suggest that FGFR1 amplification occurs more frequently in SCC and in Asians. FGFR1 amplification may be a potential new therapeutic target for specific patients and lung cancer subtypes. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that microRNAs (miRNAs) are dysregulated in esophageal squamous cell carcinoma (ESCC). Changes in miRNA expression may be associated with ESCC formation and progression. Therefore, the identification of ESCC-associated miRNAs may facilitate the development of effective therapeutic approaches for patients with ESCC. Recently, miRNA-652 (miR-652) was recognized as a cancer-associated miRNA in a number of different types of cancer. However, the expression status and roles of miR-652 in ESCC as well as the molecular mechanisms modulated or altered by it remain largely unknown. In the present study, it was demonstrated that miR-652 was downregulated in ESCC tissues and cell lines. Functional assays showed that upregulation of miR-652 expression decreased proliferation and invasion of ESCC cells. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) was determined to be a direct target of miR-652 in ESCC cells. Additionally, FGFR1 was upregulated in ESCC tissues, and the expression of FGFR1 was inversely correlated with miR-652 expression. Furthermore, restoring FGFR1 expression abolished the suppressive effects of miR-652 overexpression on the proliferation and invasion of ESCC cells. These findings demonstrated that miR-652 inhibits the proliferation and invasion of ESCC cells by directly targeting FGFR1. [ABSTRACT FROM AUTHOR]

Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1‐related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson–Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly). [ABSTRACT FROM AUTHOR]

Abstract Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

Promoting neurogenesis is a promising strategy for the treatment of cognition impairment associated with Alzheimer's disease (AD). Ganoderma lucidum is a revered medicinal mushroom for health-promoting benefits in the Orient. Here, we found that oral administration of the polysaccharides and water extract from G. lucidum promoted neural progenitor cell (NPC) proliferation to enhance neurogenesis and alleviated cognitive deficits in transgenic AD mice. G. lucidum polysaccharides (GLP) also promoted self-renewal of NPC in cell culture. Further mechanistic study revealed that GLP potentiated activation of fibroblast growth factor receptor 1 (FGFR1) and downstream extracellular signal-regulated kinase (ERK) and AKT cascades. Consistently, inhibition of FGFR1 effectively blocked the GLP-promoted NPC proliferation and activation of the downstream cascades. Our findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.•G. lucidum polysaccharides (GLP) improve cognition in transgenic AD mice•GLP promote neural progenitor proliferation and self-renewal to enhance neurogenesis•GLP potentiate FGFR signalingG. lucidum is a revered medicinal herb for promoting health. Pei and colleagues found that the polysaccharides from G. lucidum (GLP) promoted neural progenitor proliferation to enhance neurogenesis and ameliorated cognition deficits in transgenic Alzheimer's disease model mice. These findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.

Targeting fibroblast growth factor 23 (FGF-23) signaling pathway is of interest in controlling body phosphate metabolism. This study investigated the effect of anti-fibroblast growth factor receptor 1 (FGFR1, major FGF-23 receptor in the kidney) antibodies on phosphate metabolism. White Leghorn laying hens (65-wk-old) were vaccinated with either a FGFR1 peptide vaccine (five 8-amino-acid peptides were selected, CrZ-1:LPEDPRWE, CrZ-2:LDKDKPNR, CrZ-3:RRPPGMEY, CrZ-4:GSPYPGVP, and CrZ-5:RMDKPSNC) or adjuvant control. At peak antibody titer, hens were artificially inseminated. Chicks from control-vaccinated hens were fed either a non-phytate phosphorus (nPP) sufficient (nPP = 0.45%, positive control) or deficient (nPP = 0.20%, negative control) diet, while chicks from each of the FGFR1 peptide vaccinated hens were fed with the above nPP-deficient diet, for 14 D. When compared to control hens, plasma phosphate in CrZ-1, CrZ-2, CrZ-3, CrZ-4, and CrZ-5 vaccinated hens were decreased by 33, 30, 24, 20, and 26%, respectively (P < 0.05); egg weight in CrZ-2 and CrZ-5 vaccinated hens were increased by 6 and 7%, respectively (P < 0.05); egg production in CrZ-3, CrZ-4, and CrZ-5 vaccinated hens tended to decrease (P  = 0.085; decreased by 14, 15, and 13%, respectively). When compared to positive control, chicks from all other groups had decreased body weight gain (BWG) and feed intake (FI) during 1 to 14 D, and had decreased plasma phosphate, tibiotarsus ash, and 24-h phosphorus excretion on day 14. When compared to negative control, BWG of CrZ-1, CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 23, 28, 26, and 20%, respectively (P < 0.05); FI of CrZ-1, CrZ-2, and CrZ-3 antibody chicks were decreased by 15, 15, and 18%, respectively (P < 0.05); plasma phosphate of CrZ-5 antibody chicks were decreased by 26% (P < 0.05); plasma FGF-23 levels of CrZ-4 antibody chicks were increased by 18% (P < 0.05); tibiotarsus ash content of CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 20, 20, and 21%, respectively (P < 0.05). In conclusion, anti-FGFR1 peptide antibodies decreased egg production of hens and growth performance of their progeny chicks probably by activating FGF-23 signaling and stimulating FGF-23 production. [ABSTRACT FROM AUTHOR]

aim to reveal the mechanism of gefitinib resistance in NSCLC induced by FGFR1. Materials and methods: We used high-throughput sequencing to compare the mRNA expression profiles of PC9 and PC9-GR (gefitinib-resistant) cells. The clinical significance of fibroblast growth factor receptor 1 (FGFR1) in NSCLC was also investigated using immunohistochemistry and Kaplan-Meier survival analysis. Finally, the in vitro molecular mechanisms were analyzed using confocal laser microscopy, Western blotting, transwell assay, colony formation assay, CCK-8 assay, and apoptosis assay. Results: We observed that FGFR1 was highly expressed in NSCLC tissues and was closely associated with poor prognosis. Cytological experiments showed that FGFR1 promoted the proliferation and migration of PC9-GR cells and mediated their resistance to gefitinib. Furthermore, studies aimed at unraveling this mechanism revealed that FGFR1 activated the AKT/mTOR signaling pathway. These findings show that the FGFR1/AKT/mTOR signaling pathway plays a vital role in acquired resistance against gefitinib in NSCLC. Conclusion: This work provides new evidence that FGFR1 functions as a key regulator of gefitinib resistance, thereby demonstrating its potential as a novel biomarker and therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) signaling has been reported to contribute to the carcinogenic progression of various cancer types. Previous studies have demonstrated that FGFR1 expression is increased in non-small cell lung cancer (NSCLC) and promotes cancer cell metastasis. However, the molecular mechanisms underlying increased FGFR1 expression in NSCLC remains largely unknown. In the current study, microRNA (miR)-497 levels were observed to be inversely correlated with FGFR1 expression in tumor samples from patients with NSCLC. In the NSCLC cell line A549, miR-497 overexpression inhibited cell proliferation and migration. Increased expression of miR-497 led to a reduction in FGFR1 expression, at the mRNA and protein levels. In addition, transfection of miR-497 mimics inactivated the protein kinase B (AKT) and c-Jun N-terminal kinase (JNK) signaling pathways, as reduced matrix metallopeptidase 26 expression; all of which are regulated by FGFR1. Using TargetScan software, FGFR1 was also identified as a predicted target gene of miR-497, and a dual luciferase reporter assay confirmed that miR-497 directly regulated FGFR1. Transfection of a recombinant FGFR1 overexpression vector reversed miR-497 mimic-induced arrest of cell growth and migration in A549 cells. In conclusion, the results of the present study identified miR-497 as a potential tumor suppressor gene in NSCLC that may function via repressing FGFR1 expression, and AKT and JNK signaling. [ABSTRACT FROM AUTHOR]

Purpose: MicroRNA-761 (miR-761) has been reported to be deregulated in many types of human cancers and play important roles in cancer genesis and progression. However, the biological roles of miR-761 in osteosarcoma (OS) and the underlying mechanisms remain largely unknown. Methods: The expression of miR-761 in OS tissues and cell lines was analyzed using RT-qPCR. A series of gain-of-function tests were performed, and status of malignancy was evaluated on basis of proliferation, migration, invasion, and apoptosis using different assays to determine the regulatory roles of miR-761 in OS cells in vivo and in vitro. Notably, the mechanisms underlying the action of miR-761 in the pathogenesis of OS were investigated using bioinformatic analysis, luciferase reporter assay, RT-qPCR and Western blotting. Results: The results showed that miR-761 expression was decreased in OS tissues and cell lines and is closely correlated with clinical stage and distant metastasis in OS patients. Patients with OS having low miR-761 expression showed worse prognosis compared to OS patients with high miR-761 expression. Restoring the miR-761 expression level decreased OS cell proliferation, migration, and invasion in vitro; promoted cell apoptosis in vitro; and impaired tumor growth in vivo. In addition, fibroblast growth factor receptor 1 (FGFR1) was found as a direct target gene of miR-761 in OS cells. Furthermore, silencing FGFR1 expression stimulated the tumor-suppressing roles of miR-761 upregulation in OS cells, whereas the activity of miR-761 overexpression in OS cells was abolished by the restoration of FGFR1 expression. Moreover, restoration of miR-761 expression deactivated the PI3K/Akt pathway in vitro and in vivo. Conclusion: These results suggest that miR-761 plays anti-cancer roles in OS by directly targeting FGFR1 and deactivating the PI3K/Akt pathway. The newly identified miR-761/FGFR1/PI3K/Akt pathway partially illustrates the mechanism of OS pathogenesis and presents a novel candidate therapeutic target for antitumor therapy. [ABSTRACT FROM AUTHOR]

Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1‐dependent downstream signaling and FGFR1 ligand binding. To date, the major group of drugs being developed for treatment of FGFR1‐dependent cancers are small‐molecule tyrosine kinase inhibitors; however, the limited specificity of these drugs has led to increasing attempts to design molecules targeting the extracellular domain of FGFR1. Here, we used the phage display technique to select cyclic peptides F8 (ACSLNHTVNC) and G10 (ACSAKTTSAC) as binders of the fibroblast growth factor 1 (FGF1)–FGFR1 interface. ELISA and in vitro cell assays were performed to reveal that cyclic peptide F8 is more effective in preventing the FGF1–FGFR1 interaction, and also decreases FGF1‐induced proliferation of BA/F3 FGFR1c cells by over 40%. Such an effect was not observed for BA/F3 cells lacking FGFR1. Therefore, cyclic peptide F8 can act as a FGF1–FGFR1 interaction antagonist, and may be suitable for further development for potential use in therapies against FGFR1‐expressing cancer cells. [ABSTRACT FROM AUTHOR]

Aim. To identify novel FGFR1 inhibitors using the virtual screening approach. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 program package. The compounds activity was determined by in vitro biochemical tests using γ-32P ATP. Results. In vitro experiments demonstrated that 18 compounds belonging to three chemical classes had an inhibitory activity against FGFR1 with IC50 values in the range from 1.8 to 71 μM. Conclusions. Several FGFR1 inhibitors were found using molecular modeling and biochemical testing. These compounds are excellent candidates for further chemical optimization. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the role of S100B in the inflammation process during osteoarthritis (OA). OA cartilage samples were collected for S100B expression analysis. S100B expression levels were significantly increased in patients with OA compared with the Controls (1.28±0.66 vs. 0.42±0.31; P=0.01) and were determined to be correlated with TNF-α (r=0.42; P=0.04) and IL-1β (r=0.73; P=0.001) expression levels. Orthopedic casting tape was used to immobilize the right knee at 180° extension of adult female New Zealand white rabbits for 4 weeks to establish an OA model. Cartilage specimens from the medial femoral condyle of these rabbits were used for histological confirmation and immunohistochemical analyses, whereas synovial fluid was used in ELISA assays for tumor necrosis factor (TNF)-α and interleukin (IL)-1β expression levels. Human synovial fibroblasts from the knee synovial tissues of normal patients with traumatic injury were transfected with S100B overexpression and knockdown plasmids and subjected to lipopolysaccharide (LPS) stimulation; subsequently, TNF-α and IL-1β expression levels in conditioned medium were determined by ELISA; S100B overexpression and knockdown significantly increased and decreased the TNF-α and IL-1β expression levels, respectively. Increased TNF-α (573.3±15.4 vs. 102.6±8.7 pg) and IL-1β (378.6±7.2 vs. 170.1±5.8 pg) expression levels were detected in OA model rabbits compared with the Control rabbits. Additionally, S100B, fibroblast growth factor (FGF)-1 and FGF receptor (FGFR)-1 mRNA and protein expression levels were increased in OA model rabbits compared with the Control group. FGFR1 knockdown significantly decreased TNF-α and IL-1β expression levels in LPS-stimulated S100B-overexpressing human synovial fibroblasts. S100B is involved in FGFR1 signaling-mediated inflammatory response during OA, which may be considered as a potential therapeutic target. [ABSTRACT FROM AUTHOR]