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Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions.

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

Background and Aim: Antioxidants are compounds that protect cells from attacks of free radicals. Lack of balance between antioxidants and free radicals results in oxidative stress, which ultimately results in cell damage. The effects of flavonoids are not related solely to their antioxidant properties, but also to their effects on cellular signal pathways. The present study was conducted to evaluate the effect of Quercetin on the structure of the third region of FGFR2b kinase using fluorescence method. Materials and Methods: Using SDS-PAGE, expression of the protein was determined and its constant concentration was used in the present study. Using different concentrations of Quercetin in the presence of a constant concentration of pure protein, the fluorescence spectrum and chemical denaturation were evaluated. Results: In the last studies, SDS-PAGE analysis of the purified proteins had confirmed that no contamination and unwanted bacterial proteins were co-eluted with the protein. Studying the spectrum of various concentrations of Quercetin in the presence of constant concentration of proteins showed a decrease in the intensity of the release; and also, the chemical denaturation changed the third structure of the kinase domain. Conclusion: The tertiary structural change of FGFR2b kinase domain represents a conformational change that may have a critical role in signal transduction cascade. Thus, this molecular transduction inconsistency can lead to cellular transduction complication; and as a result, inhibit the development and multiplication of cancerous cells.

Purpose: We present a case of bilateral extensive peripapillary myelinated retinal nerve fibers (MRNF) in an individual with Crouzon syndrome, an inherited form of craniosynostosis caused by overactivation of fibroblast growth factor receptor 2. As a secondary aim, we examine the utility of optical coherence tomography (OCT) angiography for visualization of peripapillary vasculature obscured by myelination on other imaging modalities. Methods: A 24-year-old woman with Crouzon syndrome was evaluated for suspected optic neuritis in the right eye. Results: Funduscopic examination and photography revealed the incidental finding of bilateral extensive peripapillary MRNF. OCT angiography provided excellent visualization of peripapillary retinal vessels, which were partially obscured by myelination on other imaging modalities. Conclusions: This association of Crouzon syndrome with bilateral peripapillary MRNF may lend insight into the developmental control of optic nerve myelination, the pathogenesis of MRNF, and the potential role of growth factors in these processes. Further, OCT angiography allowed for excellent blood vessel visualization in this case of MRNF.

Major depressive disorder (MDD) is one of the most serious diseases and now becomes a major public health problem in the world. The pathogenesis of depression remains poorly understood. Fibroblast growth factors (FGFs) belong to a large family of growth factors that are involved in brain development during early periods as well as maintenance and repair throughout adulthood. In recent years, studies have found a correlation between the members of the FGF system and depression. These signaling molecules may be expected to be biomarkers for the diagnosis and prognosis of MDD, and may provide new drug targets for the treatment of depression. Here, we reviewed the correlation between some members of the FGF system and depression.

Cholangiocarcinoma is a rare type of cancer. Futibatinib is an irreversible, potent, selective inhibitor of fibroblast growth factor receptors (FGFR 1-4). On September 30, 2022, the US FDA first approved futibatinib to treat adult patients with bile duct cancer whose disease is unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene mutations or other classes of rearrangements. The approval of this medicine was based on phase 3 clinical trial results including an overall response rate (ORR) of 42% and a duration of response (DoR) of 9.7 months. This short perspective summarizes Futibatinib's synthesis, physicochemical properties, dosage, route of administration, mechanism of action, binding mode, pharmacodynamics, pharmacokinetics, drug interactions, adverse events, and possible mechanism of resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The oviduct presents the ideal conditions for fertilization and early embryonic development. In this study, (i) vascularization pattern; (ii) microvascular density; (iii) transcripts of angiogenic factors (FGF1, FGF2, VEGF) and their receptors—FGFR1, FGFR2, KDR, respectively, and (iv) the relative protein abundance of those receptors were assessed in cyclic mares’ oviducts. The oviductal artery, arterioles and their ramifications, viewed by means of vascular injection-corrosion, differed in the infundibulum, ampulla and isthmus. The isthmus, immunostained with CD31, presented the largest vascular area and the highest number of vascular structures in the follicular phase. Transcripts (qPCR) and relative protein abundance (Western blot) of angiogenic factors fibroblast growth factor 1 (FGF1) and 2 (FGF2) and vascular endothelial growth factor (VEGF), and their respective receptors (FGFR1, FGFR2, VEGFR2 = KDR), were present in all oviduct portions throughout the estrous cycle. Upregulation of the transcripts of angiogenic receptors FGF1 and FGFR1 in the ampulla and isthmus and of FGF2 and KDR in the isthmus were noted. Furthermore, in the isthmus, the relative protein abundance of FGFR1 and KDR was the highest. This study shows that the equine oviduct presents differences in microvascular density in its three portions. The angiogenic factors VEGF, FGF1, FGF2 and their respective receptors are expressed in all studied regions of the mare oviduct, in agreement with microvascular patterns.

Olfactory ensheathing cells (OECs) are a specialized class of glia, wrapping around olfactory sensory axons that target the olfactory bulb (OB) and cross the peripheral nervous system/central nervous system boundary during development and continue to do so post‐natally. OEC subpopulations perform distinct subtype‐specific functions dependent on their maturity status. Disrupted OEC development is thought to be associated with abnormal OB morphogenesis, leading to anosmia, a defining characteristic of Kallmann syndrome. Hence, anosmin‐1 encoded by Kallmann syndrome gene (KAL‐1) might modulate OEC differentiation/maturation in the OB. We performed in ovo electroporation of shRNA in the olfactory placode to knock‐down kal in chick embryos, resulting in abnormal OB morphogenesis and loss of olfactory sensory axonal innervation into OB. BLBP‐expressing OECs appeared to form a thinner and poorly organized outmost OB layer where SOX10 expressing OECs were completely absent with emergence of GFAP‐expressing OECs. Furthermore, in embryonic day 10 chick OB explant cultures, GFAP expression in OECs accumulating along the OB nerve layers was dramatically reduced by recombinant anosmin‐1. We then purified immature OECs from embryonic day 10 chick OB. These cells express GFAP after 7 days in vitro, exhibiting a multipolar morphology. Overexpression of chick anosmin, exogenous anosmin‐1 or FGF2 could inhibit GFAP expression with cells presenting elongated morphology, which was blocked by the FGF receptor inhibitor Su5402. These data demonstrate that anosmin‐1 functions via FGF signalling in regulating OEC maturation, thereby providing a permissive glial environment for axonal innervation into the OB during development. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)‐dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma‐like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF‐secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell‐recruiting cytokines. CAFs also enhanced the conversion of tumour‐associated macrophages (TAMs) to the tumour‐supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr‐independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9‐induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan‐FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR‐addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR‐amplified cell lines suggests that the anti‐proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756). What's new? Deregulated fibroblast growth factor receptor (FGFR) signaling is involved in tumorigenesis and cancer progression. Here, the authors report on a novel pan‐FGFR inhibitor, rogaratinib, that potently and highly selectively prevents the activity of FGFRs 1, 2, 3, and 4. Rogaratinib inhibits cell proliferation in various FGFR‐addicted cancers in vitro, including colon, lung, and bladder cancer. Rogaratinib also exhibits strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR mRNA overexpression with good tolerability. Altogether, these data warrant the further development of rogaratinib for treatment of cancers with FGFR alterations, and clinical trials are currently ongoing. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) comprises of neurons, which are responsible for impulse transmission, and glial cells, which surround neurons providing protection and nutrition. Glial cells are categorized into astrocytes, oligodendrocytes, microglial cells, and ependymal cells. Tumors forming from glial cells are called gliomas, and they are classified accordingly into astrocytomas, oligodendrogliomas, and ependymomas. Gliomas are characterized by high mortality rates and degree of malignancy, heterogeneity, and resistance to treatment. Among the molecular players implicated in glioma pathogenesis are members of the fibroblast growth factor (FGF) superfamily as well as their receptors (FGFRs). In the present study, we provide a review of the literature on the role of FGFs and FGFRs in glioma pathogenesis. We also demonstrate that FGFs, and particularly FGF1 and FGF2, bear a variety of mutations in gliomas, while FGFRs are also crucially involved. In fact, several studies show that in gliomas, FGFRs bear mutations, mainly in the tyrosine kinase domains. Specifically, it appears that FGFR1-TACC1 and FGFR3-TACC3 fusions are common in these receptors. A better understanding of the mutations and the molecular players involved in glioma formation will benefit the scientific community, leading to the development of more effective and innovative therapeutic approaches. [ABSTRACT FROM AUTHOR]

Résumé: Les cancers des voies biliaires (CVB) sont un groupe hétérogène de tumeurs au pronostic sombre. Dans cette revue, nous donnons un aperçu des options thérapeutiques systémiques pouvant être proposées dans les CVB avancés et des nouvelles stratégies en développement. La chimiothérapie à base de gemcitabine et de platine est le traitement standard en première ligne (L1) dans les CVB avancés. Le niveau de preuve est insuffisant pour recommander un schéma de chimiothérapie spécifique en deuxième ligne (L2), et les anticorps anti-récepteurs du facteur de croissance épidermique (EGFR) et anti-angiogéniques n'ont pas montré d'amélioration de la survie chez des patients non sélectionnés. Ces dernières années, les connaissances sur l'hétérogénéité moléculaire des CVB ont considérablement augmenté avec l'avènement des analyses génomiques et transcriptomiques à large échelle, ouvrant de nouvelles perspectives pour les stratégies de thérapies dites ciblées. Parmi les développements en cours, le ciblage des altérations du gène codant pour le récepteur du facteur de croissance des fibroblastes (FGFR) et de l'isocitrate déshydrogénase (IDH), et les immunothérapies sont les pistes les plus prometteuses. Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. In this review, we provide an overview of the systemic treatment options that can be proposed in advanced BTC and new strategies under development. Gemcitabine and platinum-based chemotherapy is the standard first-line therapy (L1) in advanced BTC. The level of evidence is insufficient to recommend a specific second-line chemotherapy regimen (L2), and anti-epidermal growth factor receptor (EGFR) and anti-angiogenic antibodies have not demonstrated any improvement in survival in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyzes, opening up new perspectives for so-called targeted therapies. Among the ongoing developments, the targeting of fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase (IDH) gene alterations, and immunotherapies are the most promising avenues. [ABSTRACT FROM AUTHOR]

• The role of tumor environment consisting of cancer cells, carcinoma associated fibroblasts and other surrounding bio-entities was explained. • The application of phage display for targeting CAFs and their GFs for cancer therapy was explored. • The modulation of FGF/FGFR signaling pathway by means of phage derived fragment antibodies, TKIs, mAbs and ligand traps was discussed. A tumor is defined as a group of cancer cells and 'surrounding' stromal bio-entities. Alongside the extracellular matrix (ECM) in the tumor microenvironment (TME), the stromal cells play key roles in cancer affliction and progression. Carcinoma-associated fibroblasts (CAFs) in the area of the tumor, whether activated or not, dictate the future of tumor cells. The CAFs and corresponding secreted growth factors (GFs), which mediate the crosstalk within the TME, can be targeted in therapies directed at the stroma. The impact of the fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling pathway in different kinds of tumors has been explored. Several tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and ligand traps targeting the formation of FGF-FGFR complex are in preclinical or early development phases. Moreover, there are numerous studies in the literature reporting the application of phage display technology for the development of peptides and proteins capable of functioning as FGF mimetics or traps, which are able to modulate FGF-related signaling pathways. In this review, prominent research in relation to phage display-assisted ligand identification for the FGF/FGFR system is discussed. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression of basic fibroblast growth factor in the matrix of human acquired cholesteatoma compared to the deep meatal skin. This topic does not appear to have been fully investigated before. Methods: An immunochemical study was conducted. Cholesteatoma tissues from adult patients were collected during surgery (n = 19). Control specimens were taken from the deep meatal skin (n = 8) and compared. Results: A highly significant difference in basic fibroblast growth factor expression was identified between cholesteatoma and skin (mean ± standard error = 58.53 ± 3.6 per cent in cholesteatoma vs 40.6 ± 3.5 per cent in skin; p = 0.005). Both basal and parabasal keratinocytes were stained positive with basic fibroblast growth factor. Additionally, there was specific staining in the basal columnar middle-ear epithelium and mast cell membrane. Conclusion: Basic fibroblast growth factor plays an active role in proliferative activity of cholesteatoma through its overexpression in basal and parabasal layers of cholesteatoma matrix. Moreover, its expression in the mast cell membrane supports its role in bone resorption activity. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most serious diseases and now becomes a major public health problem in the world. The pathogenesis of depression remains poorly understood. Fibroblast growth factors (FGFs) belong to a large family of growth factors that are involved in brain development during early periods as well as maintenance and repair throughout adulthood. In recent years, studies have found a correlation between the members of the FGF system and depression. These signaling molecules may be expected to be biomarkers for the diagnosis and prognosis of MDD, and may provide new drug targets for the treatment of depression. Here, we reviewed the correlation between some members of the FGF system and depression. [ABSTRACT FROM AUTHOR]

Effective therapies are limited for pancreatic cancer, particularly for those with distant tumour metastases. Therefore, more individualised drug screening is urgently required. Next-generation sequencing (NGS) is a powerful tool to investigate the genomic landscape of patients and the mechanism of drug response, which may provide a broader vision for potential clinical drug screening. Patient-derived xenograft (PDX) models may have a significant advantage in predicting clinical treatment response. In our previous study, a PDX of pancreatic cancer bone metastasis was established, and NGS was conducted to investigate the molecular information. In the present study, these data were further analysed and fibroblast growth factor receptor 1 (FGFR1) amplification was identified in a panel of 416 cancer-associated genes. Thus, AZD4547, an inhibitor against FGFR, was selected as a potential therapy, and was evaluated using the PDX model. AZD4547 was shown to exhibit antitumor activity by reducing the expression of FGFR1 and its targets. The present study also demonstrated the high potential of the novel NGS/PDX-based drug screening platform to improve individualised cancer treatment. [ABSTRACT FROM AUTHOR]

Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor. In this study, we investigated the cause of the limited therapeutic effect of the MEK inhibitor, selumetinib, in head and neck squamous cell carcinoma cells. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. [ABSTRACT FROM AUTHOR]

Approved fibroblast growth factor receptor (FGFR) inhibitors include erdafitinib, pemigatinib, and futibatinib. We review the most common toxicities associated with FGFR inhibitors and provide practical advice regarding their management. Hyperphosphatemia can be managed with careful monitoring, dose reduction or interruption, a prophylactic low-phosphate diet, and phosphate-lowering therapy. Ocular adverse events (AEs) are managed by withholding or adjusting the dose of the FGFR inhibitor. Dermatologic AEs include alopecia, which can be managed with minoxidil, and dry skin, which can be treated with moisturizers. Hand-foot syndrome can be prevented by lifestyle changes and managed with moisturizing creams, urea, or salicylic acid. Among gastrointestinal AEs, diarrhea may be managed with loperamide; stomatitis can be managed with baking soda rinses, mucosa-coating agents, and topical anesthetics; and dry mouth may be alleviated with salivary stimulants. Most FGFR inhibitor-associated toxicities are manageable with prophylactic measures and treatments; proactive monitoring is key to ensuring optimal clinical benefits., Competing Interests: Declaration of interests V.S. was affiliated with UT MD Anderson Cancer Center at the time of submission. At the time of submission, V.S. reports a consulting or advisory role with Incyte Corporation; grants from Eli Lilly/Loxo Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics, and Boston Pharmaceuticals; research funding and a consulting or advisory role with Eli Lilly/Loxo Oncology; research funding from Roche/Genentech, Bayer, GlaxoSmithKline, Helsinn Pharmaceuticals, NanoCarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum Q10, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCICTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, and MedImmune; an advisory board/consultant position with Helsinn, Incyte Corporation, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Janssen, Relay Therapeutics, Roche, and MedImmune; travel funds from Pharmamar, Incyte Corporation, ASCO, and ESMO; and other support from Medscape. S.V. has received honoraria and research support from Incyte Corporation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1-FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well-known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)