RESUMO
FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors, and a kinase dead allele of Fgfr2 that broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, we identified discrete functions for signaling pathways in specific craniofacial contexts, but point mutations, even when combined, failed to recapitulate the single or double null mutant phenotypes. Furthermore, the signaling mutations abrogated established FGF-induced signal transduction pathways, yet FGF functions such as cell-matrix and cell-cell adhesion remained unaffected, though these activities did require FGFR kinase activity. Our studies establish combinatorial roles of Fgfr1 and Fgfr2 in development and uncouple novel FGFR kinase-dependent cell adhesion properties from canonical intracellular signaling.
Assuntos
Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Transdução de Sinais/genética , Animais , Adesão Celular/genética , Morte Celular/genética , Células Cultivadas , Camundongos , Mutação , Crista Neural/citologia , Proteínas Quinases/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood. Here, we characterized fibroblast growth factor receptor (FGFR) tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. Our data show that gatekeeper mutations destabilize the autoinhibitory conformation of the DFG motif locally and of the kinase globally, suggesting they impart gain-of-function by facilitating the kinase's ability to populate the active state.
Assuntos
Neoplasias , Receptores Proteína Tirosina Quinases , Humanos , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias/tratamento farmacológico , Mutação , Trifosfato de Adenosina/uso terapêutico , Tirosina , Inibidores de Proteínas Quinases/químicaRESUMO
Fibroblast Growth Factor Receptor (FGFR) is connected to numerous downstream signalling cascades regulating cellular behavior. Any dysregulation leads to a plethora of illnesses, including cancer. Therapeutics are available, but drug resistance driven by gatekeeper mutation impedes the treatment. Ponatinib is an FDA-approved drug against BCR-ABL kinase and has shown effective results against FGFR-mediated carcinogenesis. Herein, we undertake molecular dynamics simulation-based analysis on ponatinib against all the FGFR isoforms having Val to Met gatekeeper mutations. The results suggest that ponatinib is a potent and selective inhibitor for FGFR1, FGFR2, and FGFR4 gatekeeper mutations. The extensive electrostatic and van der Waals interaction network accounts for its high potency. The FGFR3_VM mutation has shown resistance towards ponatinib, which is supported by their lesser binding affinity than wild-type complexes. The disengaged molecular brake and engaged hydrophobic spine were believed to be the driving factors for weak protein-ligand interaction. Taken together, the inhibitory and structural characteristics exhibited by ponatinib may aid in thwarting resistance based on Val-to-Met gatekeeper mutations at an earlier stage of treatment and advance the design and development of other inhibitors targeted at FGFRs harboring gatekeeper mutations.
Assuntos
Imidazóis , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Piridazinas , Piridazinas/química , Piridazinas/farmacologia , Piridazinas/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Colangiocarcinoma , Pirazóis , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Adulto , Quinoxalinas/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Povo Asiático , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Intervalo Livre de Progressão , Idoso de 80 Anos ou maisRESUMO
FGF homologous factors (FHFs) are the least described group of fibroblast growth factors (FGFs). The FHF subfamily consists of four proteins: FGF11, FGF12, FGF13, and FGF14. Until recently, FHFs were thought to be intracellular, non-signaling molecules, despite sharing structural and sequence similarities with other members of FGF family that can be secreted and activate cell signaling by interacting with surface receptors. Here, we show that despite lacking a canonical signal peptide for secretion, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to the unconventional secretion of FGF2. The secreted FHFs are biologically active and trigger signaling in cells expressing FGF receptors (FGFRs). Using recombinant proteins, we demonstrated their direct binding to FGFR1, resulting in the activation of downstream signaling and the internalization of the FHF-FGFR1 complex. The effect of receptor activation by FHF proteins is an anti-apoptotic response of the cell.
Assuntos
Fatores de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Fosforilação , Processamento de Proteína Pós-TraducionalRESUMO
Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized. Here we delineate the role of mitotic kinases in receptor trafficking during asymmetric division. Targeted perturbations reveal that Cyclin-dependent Kinase 1 (CDK1) and Aurora Kinase promote storage of Fibroblast Growth Factor Receptors (FGFRs) by suppressing endosomal degradation and recycling pathways. As cells progress through metaphase, loss of CDK1 activity permits differential degradation and targeted recycling of stored receptors, leading to asymmetric induction. Mitotic receptor storage, as delineated in this study, may facilitate rapid reestablishment of signaling competence in nascent daughter cells. However, mutations that limit or enhance the release of stored signaling components could alter daughter cell fate or behavior thereby promoting oncogenesis.
Assuntos
Aurora Quinases/fisiologia , Proteína Quinase CDC2/fisiologia , Mitose/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Animais Geneticamente Modificados , Aurora Quinases/genética , Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/metabolismo , Ciona intestinalis/embriologia , Ciona intestinalis/genética , Embrião não Mamífero , Mitose/genética , Transporte Proteico/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/genética , Distribuição Tecidual/genéticaRESUMO
Alterations of fibroblast growth factor receptors (FGFRs) are common in bladder and other cancers and result in disrupted signalling via several pathways. Therapeutics that target FGFRs have now entered the clinic, but, in common with many cancer therapies, resistance develops in most cases. To model this, we derived resistant sublines of two FGFR-driven bladder cancer cell lines by long-term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole-exome sequencing. We identified several resistance-associated molecular profiles. These included HRAS mutation in one case and reversible mechanisms resembling a drug-tolerant persister phenotype in others. Upregulated IGF1R expression in one resistant derivative was associated with sensitivity to linsitinib and a profile with upregulation of a YAP/TAZ signature to sensitivity to the YAP inhibitor CA3 in another. However, upregulation of other potential therapeutic targets was not indicative of sensitivity. Overall, the heterogeneity in resistance mechanisms and commonality of the persister state present a considerable challenge for personalised therapy. Nevertheless, the reversibility of resistance may indicate a benefit from treatment interruptions or retreatment following disease relapse in some patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Recidiva Local de Neoplasia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de Sinais , Linhagem Celular TumoralRESUMO
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody-drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents.
Assuntos
Neoplasias dos Ductos Biliares , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Estados Unidos , Humanos , Receptores de Fatores de Crescimento de Fibroblastos/genética , Terapia de Alvo Molecular , Ductos Biliares Intra-Hepáticos , TirosinaRESUMO
BACKGROUND: Fibroblast growth factor receptor-3 (FGFR3) gain-of-function mutations are linked to achondroplasia. Infigratinib, a FGFR1-3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro-computed tomography, histology, and immunohistochemistry. RESULTS: Mandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle. CONCLUSIONS: High dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies.
Assuntos
Acondroplasia , Camundongos , Masculino , Ratos , Feminino , Animais , Microtomografia por Raio-X , Ratos Wistar , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
The clinical management of metastatic urothelial carcinoma (mUC) is undergoing a major paradigm shift; the integration of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) into the mUC therapeutic strategy has succeeded in improving platinum-based chemotherapy outcomes. Given the expanding therapeutic armamentarium, it is crucial to identify efficacy-predictive biomarkers that can guide an individual patient's therapeutic strategy. We reviewed the literature data on mUC genomic alterations of clinical interest, discussing their prognostic and predictive role. In particular, we explored the role of the fibroblast growth factor receptor (FGFR) family, epidermal growth factor receptor 2 (HER2), mechanistic target of rapamycin (mTOR) axis, DNA repair genes, and microsatellite instability. Currently, based on the available clinical data, FGFR inhibitors and HER2-directed ADCs are effective therapeutic options for later lines of biomarker-driven mUC. However, emerging genomic data highlight the opportunity for earlier use and/or combination with other drugs of both FGFR inhibitors and HER2-directed ADCs and also reveal additional potential drug targets that could change mUC management.
Assuntos
Receptor ErbB-2 , Humanos , Receptor ErbB-2/análise , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/secundário , Genômica/métodos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Biomarcadores Tumorais/genética , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Instabilidade de MicrossatélitesRESUMO
Among the three embryonic germ layers, the mesoderm plays a central role in the establishment of the vertebrate body plan. The mesoderm is specified by secreted signaling proteins from the FGF, Nodal, BMP and Wnt families. No new classes of extracellular mesoderm-inducing factors have been identified in more than two decades. Here, we show that the pinhead (pnhd) gene encodes a secreted protein that is essential for the activation of a subset of mesodermal markers in the Xenopus embryo. RNA sequencing revealed that many transcriptional targets of Pnhd are shared with those of the FGF pathway. Pnhd activity was accompanied by Erk phosphorylation and required FGF and Nodal but not Wnt signaling. We propose that during gastrulation Pnhd acts in the marginal zone to contribute to mesoderm heterogeneity via an FGF receptor-dependent positive feedback mechanism.
Assuntos
Mesoderma/embriologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Proteínas de Xenopus/metabolismo , Animais , Mesoderma/citologia , RNA-Seq , Receptores de Fatores de Crescimento de Fibroblastos/genética , Fator de Crescimento Transformador beta/genética , Proteínas de Xenopus/genética , Xenopus laevisRESUMO
Nascent myotubes undergo a dramatic morphological transformation during myogenesis, in which the myotubes elongate over several cell diameters and are directed to the correct muscle attachment sites. Although this process of myotube guidance is essential to pattern the musculoskeletal system, the mechanisms that control myotube guidance remain poorly understood. Using transcriptomics, we found that components of the Fibroblast Growth Factor (FGF) signaling pathway were enriched in nascent myotubes in Drosophila embryos. Null mutations in the FGF receptor heartless (htl), or its ligands, caused significant myotube guidance defects. The FGF ligand Pyramus is expressed broadly in the ectoderm, and ectopic Pyramus expression disrupted muscle patterning. Mechanistically, Htl regulates the activity of Rho/Rac GTPases in nascent myotubes and effects changes in the actin cytoskeleton. FGF signals are thus essential regulators of myotube guidance that act through cytoskeletal regulatory proteins to pattern the musculoskeletal system.
Assuntos
Padronização Corporal/genética , Drosophila/embriologia , Fatores de Crescimento de Fibroblastos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Ectoderma/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/genética , Ligantes , Masculino , Desenvolvimento Musculoesquelético/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética , Proteínas rac de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Fibroblast growth factors (FGFs) are key factors affecting diabetic wound healing. However, the FGF family's expression patterns in skin and wounds influenced by both diabetes and sex are still unknown. METHODS AND RESULTS: In this study, normal and Streptozotocin (STZ)-induced type 1 diabetic C57BL/6J male and female mice were used to study the FGF family's expression in non-wound skin and wounds. We found that the expression patterns of Fgfs were affected by sex in both normal and diabetic animals during wound healing. In normal control mice, sex difference had a limited effect on basal skin Fgf expressions. However, it significantly influenced Fgf expressions in wounds. Type 1 diabetes reduced basal and wound-induced skin Fgf expressions. Female mice had far lower wound-induced skin Fgf expressions in diabetic mice. In addition, sex differently influenced Fibroblast growth factors receptor (Fgfr) expression patterns of non-wound skin and wounds in both normal and diabetic mice. Moreover, female mice had a lower relative level of Fibronectin leucine-rich repeat transmembrane protein 2 (FLRT2) - a FGFR activation marker gene - in wound and blood plasma. Correspondingly, the wound areas of female animals were larger than that of male animals in the early stage of wound healing (less than 3-day injury). CONCLUSION: Our research shows that the FGF family have different expression patterns in normal and diabetic wound healing in mice of different sex. Additionally, we also provide the signatures of individual FGFs in diabetic wound healing, which deserve further investigation.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Camundongos , Feminino , Masculino , Animais , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Estreptozocina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Caracteres Sexuais , Camundongos Endogâmicos C57BL , Pele/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Glicoproteínas de Membrana/metabolismoRESUMO
The number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.
Assuntos
Proteínas de Drosophila/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Mioblastos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator de Transcrição TFIID/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila , Proteínas de Drosophila/genética , Desenvolvimento Muscular , Mioblastos/citologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas de Ligação a RNA/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fator de Transcrição TFIID/genéticaRESUMO
The morbidity and mortality of prostate cancer are increasing year by year, and the survival rate of prostate cancer patients after treatment is low. Therefore, investigating the molecular mechanism underlying prostate cancer is crucial for developing effective treatments. Recent studies have shown the important role of long-chain non-coding RNAs (lncRNAs) in tumorigenesis. VPS9D1-AS1 can modulate the progression of multiple cancers, but its molecular action mechanism in prostate cancer remains unknown. This study, therefore, intended to investigate the regulatory mechanism of VPS9D1-AS1 in prostate cancer. First, differentially expressed lncRNAs in prostate cancer were identified through bioinformatics approaches. The target lncRNA for the study was determined by reviewing the relevant literature and its downstream miRNA/mRNA axis was uncovered. Then, quantitative reverse transcription polymerase chain reaction was introduced to assess the expression of VPS9D1-AS1, miR-187-3p, and fibroblast growth factor receptor-like 1 (FGFRL1) at a cellular level, and Western blot was conducted to assess the protein level of FGFRL1 in cells. The results indicated that VPS9D1-AS1 and FGFRL1 were highly expressed in prostate cancer while miR-187-3p was less expressed. Besides, MTT, colony formation, wound healing, and cell invasion assays showed that silencing VPS9D1-AS1 inhibited the viability, migration ability, and invasion ability of prostate cancer cells. Dual-luciferase assay and RNA binding protein immunoprecipitation assay were performed to explore the interplay of miR-187-3p and VPS9D1-AS1 or FGFRL1. The results showed that VPS9D1-AS1 could sponge miR-187-3p, and FGFRL1 could serve as a direct target of miR-187-3p. Moreover, combined with the results of the rescue experiment, VPS9D1-AS1 was found to upregulate FGFRL1 by competitively sponging miR-187-3p to accelerate the malignant behaviors of prostate cancer cells. In conclusion, VPS9D1-AS1 could promote the phenotype progression of prostate cancer cells through targeting the miR-187-3p/FGFRL1 axis, and it has the potential to be a target for prostate cancer patients.
Assuntos
MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Fibroblast growth factors (FGFs) encode a large family of growth factor proteins that activate several intracellular signaling pathways to control diverse physiological functions. The human genome encodes 22 FGFs that share a high sequence and structural homology with those of other vertebrates. FGFs orchestrate diverse biological functions by regulating cellular differentiation, proliferation, and migration. Dysregulated FGF signaling may contribute to several pathological conditions, including cancer. Notably, FGFs exhibit wide functional diversity among different vertebrates spatiotemporally. A comparative study of FGF receptor ligands and their diverse roles in vertebrates ranging from embryonic development to pathological conditions may expand our understanding of FGF. Moreover, targeting diverse FGF signals requires knowledge regarding their structural and functional heterogeneity among vertebrates. This study summarizes the current understanding of human FGF signals and correlates them with those in mouse and Xenopus models, thereby facilitating the identification of therapeutic targets for various human disorders.
Assuntos
Fatores de Crescimento de Fibroblastos , Neoplasias , Humanos , Animais , Camundongos , Xenopus laevis/metabolismo , Ligantes , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Desenvolvimento Embrionário/genética , Neoplasias/genéticaRESUMO
The addition of new neurons to existing neural circuits in the adult brain remains of great interest to neurobiology because of its therapeutic implications. The premier model for studying this process has been the hippocampal dentate gyrus in mice, where new neurons are added to mature circuits during adulthood. Notably, external factors such as an enriched environment (EE) and exercise markedly increase hippocampal neurogenesis. Here, we demonstrate that EE acts by increasing fibroblast growth factor receptor (FGFR) function autonomously within neurogenic cells to expand their numbers in adult male and female mice. FGFRs activated by EE signal through their mediators, FGFR substrate (FRS), to induce stem cell proliferation, and through FRS and phospholipase Cγ to increase the number of adult-born neurons, providing a mechanism for how EE promotes adult neurogenesis.SIGNIFICANCE STATEMENT How the environment we live in affects cognition remains poorly understood. In the current study, we explore the mechanism underlying the effects of an enriched environment on the production of new neurons in the adult hippocampal dentate gyrus, a brain area integral in forming new memories. A mechanism is provided for how neural precursor cells in the adult mammalian dentate gyrus respond to an enriched environment to increase their neurogenic output. Namely, an enriched environment acts on stem and progenitor cells by activating fibroblast growth factor receptor signaling through phospholipase Cγ and FGF receptor substrate proteins to expand the pool of precursor cells.
Assuntos
Meio Ambiente , Hipocampo/citologia , Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
Fibroblast growth factor receptor inhibitors (FGFRi) were introduced into clinical trials on several cancer types and found to be particularly efficacious on urothelial cancer and cholangiocarcinoma. Although many enrolled patients responded well in clinical trials, there were some patients who did not respond to FGFRi even though their tumors carried the genomic changes that met the enrollment criteria. As already established, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) share the downstream signaling pathway of MAPK activation. Accordingly, it is conceivable that targeted inhibition of FGFR alone could leave the MAPK signaling unaffected when the signaling through EGFR is relatively strong. To test this hypothesis, we calculated here the FGFR to EGFR mRNA ratio (F/E for short) of biliary tract and urothelial cancer cell lines utilized in preclinical studies. In six biliary tract cancer cell lines, two responsive lines had an F/E of 9.5 and 9.0, whereas the F/E of four nonresponsive lines was 0.1-1.8. In 22 urothelial cancer cell lines, four of the five responsive lines showed an F/E of 2.8-4.9 (median, 3.6), whereas the F/E range of 17 nonresponsive lines was 0.01-2.7 (median, 0.6) (p = 0.004). We further investigated our 47 patient-derived colorectal cancer-stem cell spheroid lines. The 18 responsive lines showed relatively high F/E (median, 16.4), whereas 29 nonresponsive lines had low F/E (median, 9.2) (p = 0.0006). These results suggest that F/E is another strong predictor of responses to FGFRi that is as useful as the current genomic criteria based solely on the FGFR genomic changes.
Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Transdução de Sinais , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.
Assuntos
Neoplasias do Colo , Inibidores de Proteínas Quinases , Animais , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dano ao DNA , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).