Fibroblast Growth Factor Receptor Inhibitors Research Articles

Structure–Activity Relationship Studies of Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine Derivatives to Develop Selective FGFR Inhibitors as Anticancer Agents for FGF19-overexpressed Hepatocellular Carcinoma

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).

Virtual screening and lead optimization of Desmostachya bipinnata-derived FGFR inhibitors for oral squamous cell carcinoma management

BackgroundOral cancer remains a major global health challenge with limited therapeutic options, highlighting the need for novel treatments. Phytochemicals derived from Desmostachya bipinnata (Db), a plant used in traditional Chinese medicine for its anti-inflammatory and analgesic properties, have demonstrated potential anti-cancer effects. However, their mechanisms of action, particularly in targeting Fibroblast Growth Factor Receptor (FGFR) in oral cancer, are not well characterized. ObjectiveThis study aimed to leverage in-silico drug design methodologies to identify bioactive compounds from Db with potential FGFR-inhibiting activity for the treatment of oral cancer. MethodologyAn MTT assay was conducted using KB cell lines to evaluate cytotoxic effects, while thirty-eight phytochemicals from Db were screened through in silico approaches for their pharmacokinetics, toxicity, and drug-likeness. Molecular docking studies were performed to assess binding affinities to the FGFR protein. The biological activity and toxicity of the compounds were predicted to prioritize candidates for further investigation. ResultsFourteen compounds were identified as promising candidates based on their drug-like properties, favourable pharmacokinetic profiles, significant FGFR binding affinities, and predicted anti-cancer activity. These compounds also demonstrated potential for oral bioavailability and central nervous system penetration, supporting their candidacy for further drug development. Notably, the traditional use of Desmostachya bipinnata in TCM emphasizes its role in enhancing overall vitality and immune function, which may synergize with the identified FGFR-inhibiting properties in the context of oral cancer treatment ConclusionThe phytochemicals from Desmostachya bipinnata exhibit significant potential as FGFR-targeted therapeutic agents for oral cancer. Further experimental validation and optimization of these lead compounds could contribute to the development of novel, effective treatments for oral cancer and related conditions

Cataracts Associated With Fibroblast Growth Factor Receptor Inhibitors for Cholangiocarcinoma

Since fibroblast growth factor receptor inhibitors (FGFRi) are used for treatment of intrahepatic cholangiocarcinoma (iCCA), understanding potential complications following longer-term use in clinical practice settings is warranted. This study describes cataract formation or progression as a complication of FGFRi use for the treatment of iCCA, even after treatment discontinuation. To describe cases of cataract formation or worsening in patients with iCCA treated with FGFRi and to characterize the ophthalmologic features, risk factors, and outcomes for FGFRi-associated cataracts. This retrospective case series study used data from patients with iCCA harboring FGFR2 aberrations who received FGFRi in clinical trials or as standard therapy from the University of California, San Francisco, Hepatobiliary Tissue Bank and Registry. Data were collected from patient visits between February 2015 and October 2021, and this retrospective investigation was conducted from September 6, 2022, to May 4, 2023. Data analysis was conducted from May 5, 2023, to September 6, 2023. Use of an FGFRi for the treatment of iCCA. The primary outcome was designated as development of a new or worsening cataract after FGFRi initiation. Statistical analysis for the association between cataract formation and clinical covariates was performed using unpaired t tests and Fisher exact tests. A single bivariate logistic regression model was used to examine total duration of FGFRi therapy and age at the conclusion of FGFRi therapy as predictors of cataract development. A total of 18 patients were included in the study; median (range) patient age was 54 (27-81) years, and 13 patients (72%) were female. Nine patients (50%) developed a cataract or had cataract progression in at least 1 eye after initiation of FGFRi. Of 17 eyes with cataract, 8 eyes (47%) required cataract surgery. One patient rapidly developed a cataract associated with phacomorphic glaucoma, which required urgent surgery. The median (range) time to cataract onset or worsening from initiation of FGFRi was approximately 18 (1-23) months. Five of 9 patients (56%) who developed cataracts or had cataract progression were diagnosed with new or worsening cataracts after discontinuation of FGFRi. Patients who developed cataracts had longer median (range) duration of FGFRi treatment compared with patients who did not develop cataracts (13 months [2-26] vs 5 months [1-11]; odds ratio, 1.01; 95% CI, 1.00-1.02; P = .02). While this retrospective case series study cannot prove cause and effect conclusively due to the study design, study results highlight cataract formation or progression as a potential adverse effect of FGFRi therapy, supporting consideration of periodic eye examinations in patients who have received this treatment.

Fibroblast Growth Factor Receptor 1-Specific Dehydrogelation to Release Its Inhibitor for Enhanced Lung Tumor Therapy.

Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (Nap-Y), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib (Nin) to form a peptide hydrogel Gel Y/Nin for localized administration and FGFR1-triggered release of Nin. Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Y in Gel Y/Nin is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H2PO3)-OH (Nap-Yp), leading to dehydrogelation of the gel and subsequent Nin release. In vitro experiments demonstrate that the release of Nin in a sustained manner from Gel Y/Nin significantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that Gel Y/Nin exhibits enhanced therapeutic efficacy on lung tumor than free Nin. We anticipate that Gel Y/Nin will be utilized for lung cancer treatment in clinical settings in the near future.

7434 Modulation of FGFR-FGF2-FGF23 Signaling Partially Rescues Osteoarthritis in Hyp Mice Homolog of Human X- Linked Hypophosphatemia

Abstract Disclosure: M.M. Hurley: None. L. Xiao: None. Human with X-linked hypophosphatemia (XLH) and its Hyp mice homolog develop several phenotypic abnormalities due to phosphate wasting mediated by abnormal Fibroblast Growth Factor Receptor-1 (FGFR1) and Fibroblast Growth Factor 23 (FGF23) signaling. XLH and Hyp mice also develop severe osteoarthropathy (OA) whose etiology is not fully defined. We previously reported that Fibroblast growth factor 2 (FGF2) regulates FGF23, specifically, mice overexpressing the high molecular weight FGF2 isoforms (HMWFGF2) in osteoprogenitors phenocopy Hyp mice including development of OA that worsens with age. Since we also reported that Hyp mice overexpress HMWFGF2 isoforms in osteoblasts and osteocytes, we examined whether the knee OA phenotype in Hyp mice was associated with aberrant FGFR1, FGF2, FGF23 signaling in knee joint articular cartilage and subchondral bone and whether in vivo FGFR tyrosine kinase inhibitor BGJ398 would modulate the OA phenotype in knee joints of Hyp mice. Ten weeks-old Control and Hyp mice were treated with Vehicle or BGJ398 for 12 weeks. Safranin-O staining of knee articular cartilage for proteoglycan revealed decreased staining in Hyp vehicle-treated mice that was partially restored to the cartilage thickness of Control mice in the Hyp-BGJ398-treated group. Significantly increased degradative enzyme matrix metalloproteinase-13 (MMP-13) in Hyp vehicle-treated knee articular cartilage was significantly reduced by BGJ398. Immunostaining revealed significantly increased phosphorylated FGFR1, FGF2 and FGF23 in both articular cartilage and subchondral bone. While BGJ398 significantly reduced immunostaining for phosphoFGFR1 and FGF2 in both articular cartilage and subchondral bone, it significantly reduced FGF23 in subchondral bone but not in articular cartilage. Significantly increased phospho-ERK1/2 labeling in Hyp-vehicle treated articular cartilage was partially rescued by BGJ398. This study demonstrates that increased FGFR1/FGF2 signaling contributes to OA in Hyp mice that can be partially rescued by FGF receptor inhibitor via reduction in MAPK signaling. Presentation: 6/1/2024

FGFR2-fusions define a clinically actionable molecular subset of pancreatic cancer

Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.

Expert Consensus on the Diagnosis and Treatment of FGFR Gene-Altered Solid Tumors

AbstractThe fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

New drug combination regimen based on pharmacokinetic characteristics—Erdafitinib combined with sertraline or duloxetine

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

New Advances in Metastatic Urothelial Cancer: A Narrative Review on Recent Developments and Future Perspectives.

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.

Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first- and second-generation, non-covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR-R1PCa cell lines to second-generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). 2D and 3D mono- and co-cultures of cancer cells, and cancer-associated fibroblasts (CAFs) were used to mimic tumor-stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real-time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. The FGFRis were more effective in mono-cultures of the cancer cells compared with co-cultures with CAFs. The FRS2αi was specifically effective in co-cultures with CAFs but was not cytotoxic to CAF mono-cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p-FRS2α, p-ERK1/2, and activated apoptosis as monitored by cleaved caspase-3 activity in a concentration-dependent manner in the co-cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co-cultures as indicated by their reduced size and Ki67 expression. CAFs exert a protective effect on cancer cells and should be included in the invitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co-cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next-generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.

Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor1 inhibitors and anticancer agents.

Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series of FGFR-1 targeting cancer. The designed series was synthesized and submitted to NCI-USA to be screened for their growth inhibitory activity on NCI cancer cell lines. Some of the synthesized hybrids displayed promising growth inhibitory activity on NCI cancer cell lines with a mean GI% between 70.39% and a lethal effect. Compounds 9a, 9i, 9j, and 9n-p were further selected for a five-dose assay and all the tested candidates showed promising antiproliferative activity with GI50 reaching the submicromolar range. Encouraged by the potent activity of 9a on colon cancer on the one hand and the well-known overexpression of FGFR-1 in it on the other hand, it was further selected as a representative example to be evaluated for its mechanism on the cell cycle and apoptosis of HCT116 cell line. Interestingly, 9a was found to pause the cell cycle of the HCT116 cell line at the G1 phase and induced late apoptosis. In parallel, all the synthesized hybrids 9a-p were examined for their potential to inhibit FGFR-1 at 10 µM. Compounds 9a, 9g, 9h, and 9p were found to have potent inhibitory activity with % inhibition = 63.04%, 58.31%, 60.87% and 79.84%, respectively. Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

Synthesis and Biological Evaluation of Thiazole-based Fibroblast Growth Factor Receptor-1 Inhibitors.

The Fibroblast Growth Factor Receptor-1 (FGFR-1) is a tyrosine kinase and a validated target for the treatment of different cancer types. Design and synthesis of novel thiazole-based analogues of anticancer agents. Series of 2-aryl-5-methylthiazole analogues linked to structurally variable basic heads were synthesized as novel anticancer agents. Developed compounds were tested for their cytotoxic activities against several cancer cell lines. Many analogues exhibited strong antiproliferative activities against breast cancer cell lines, with higher potency towards the highly metastatic form (MDA-MB-231). Pharmacophoric profiling using an in-house pharmacophore database identified FGFR-1 as a molecular target of active analogues. Synthesized compounds were bioassayed for their FGFR-1 inhibitory activities and many hits exhibited IC50 values in the low micromolar to nanomolar range. The 2-aryl-5-methylthiazole linked to a basic head is a novel chemical scaffold of ATP-competitive inhibitor of FGFR-1 with potential therapeutic activities against different types of cancer.

FGFR1-mediated enhancement of foot-and-mouth disease virus entry

Foot-and-mouth disease virus (FMDV), a member of picornavirus, can enter into host cell via macropinocytosis. Although it is known that receptor tyrosine kinases (RTKs) play a crucial role in FMDV macropinocytic entry, the specific RTK responsible for regulating this process and the intricacies of RTK-mediated downstream signaling remain to be elucidated. Here, we conducted a screening of RTK inhibitors to assess their efficacy against FMDV. Our findings revealed that two compounds specifically targeting fibroblast growth factor receptor 1 (FGFR1) and FMS-like tyrosine kinase 3 (FLT3) significantly disrupted FMDV entry. Furthermore, additional evaluation through gene knockdown and overexpression confirmed the promotion effect of FGFR1 and FLT3 on FMDV entry. Interestingly, we discovered that the increasement of FMDV entry facilitated by FGFR1 and FLT3 can be ascribed to increased macropinocytic uptake. Additionally, in-depth mechanistic study demonstrated that FGFR1 interacts with FMDV VP3 and undergoes phosphorylation during FMDV entry. Furthermore, the FGFR1 inhibitor inhibited FMDV-induced activation of p21-activated kinase 1 (PAK1) on Thr212 and Thr423 sites. Consistent with these findings, the ectopic expression of FGFR1 resulted in a concomitant increase in phosphorylation level of PAK1 on Thr212 and Thr423 sites. Taken together, our findings represent the initial exploration of FGFR1's involvement in FMDV macropinocytic entry, providing novel insights with potential implications for the development of antiviral strategies.

Exploring the Horizon: Anti-Fibroblast Growth Factor Receptor Therapy in Pancreatic Cancer with Aberrant Fibroblast Growth Factor Receptor Expression-A Scoping Review.

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations.

Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches

Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.

Inhibiting FGFR by toadflax reverses erlotinib resistance in nonsmall cell lung cancer

This study aims to demonstrate the effect of toadflax (bufalin) on erlotinib resistance in nonsmall cell lung cancer (NSCLC) by inhibiting the fibroblast growth factor receptor (FGFR). The microfluidic mobility transferase and caliper mobility-shift assays were employed to detect the FGFR inhibition by bufalin and the binding reversibility. Further, the inhibitory effects of bufalin were determined in HCC827 and HCC827/ER cells in vitro, investigating relative FGFR overexpression by quantitative reverse transcriptase-PCR (RT-qPCR) and FGFR downstream proteins, that is, FGFR substrate 2 (FRS2), extracellular signal-regulated kinase (ERK), and S6 by western blot analysis. Finally, HCC827/ER-inoculated xenograft tumors were constructed to observe the effects of bufalin and bufalin + erlotinib intervention on tumor growth. Bufalin inhibited FGFR by reversibly binding to FGFR1. In addition, the western blot analysis indicated a significant reduction in the expression levels of FGFR, FRS2, ERK, and S6 proteins in HCC827 and HCC827/ER cells, increasing the expression levels of apoptotic caspase-3 and poly-(ADP-ribose) polymerase proteins. Bufalin + erlotinib combination significantly inhibited the apoptosis of HCC827/ER cells and subsequent tumor growth in vivo. In addition, FGFR overexpression significantly reversed the sensitivity of bufalin to HCC827/ER cells, promoting the value-addition of HCC827/ER cells. Further, bufalin + erlotinib significantly reduced the growth of erlotinib-resistant HCC827/ER tumors, induced apoptosis, and inhibited the expression of FGFR and p-ERK proteins. These findings indicated that bufalin could reverse the erlotinib resistance in NSCLC by inhibiting the FGFR expression.

Ocular surface adverse reactions of antitumor-targeted drugs

With the extensive application of targeted drugs, the survival rate of cancer patients has been significantly improved. However, adverse reactions to the drugs have also become apparent, especially those affecting the ocular surface, which can severely impact patients' vision and quality of life. The article systematically analyzes a variety of targeted drugs, including epidermal growth factor receptor inhibitors, human epidermal growth factor receptor 2 inhibitors, fibroblast growth factor receptor inhibitors, selective estrogen receptor modulators, vascular endothelial growth factor receptor inhibitors, aromatase inhibitors, proteasome inhibitors, antibody-drug conjugates, Bruton's tyrosine kinase inhibitors, FMS-like tyrosine kinase 3 inhibitors, and cyclin-dependent kinase inhibitors, and discusses their adverse reactions on the ocular surface. The review emphasizes the role of clinicians in monitoring and managing patients' ocular surface health and the importance of early diagnosis and intervention to ensure that patients receive optimal visual protection while undergoing antitumor treatment.

Effects of Food, Gastric Acid Reduction, and Strong CYP3A Induction on the Pharmacokinetics of Tasurgratinib, a Novel Selective Fibroblast Growth Factor Receptor Inhibitor.

We conducted this three-part study in healthy subjects to investigate the pharmacokinetics of tasurgratinib (orally available selective inhibitor of fibroblast growth factor receptor 1-3) and M2 (its major metabolite) under different conditions. In Part A, subjects received tasurgratinib 35 mg either fed with a high-fat meal or fasted. In Parts B and C, subjects received tasurgratinib 35 mg alone or with either rabeprazole (acid-reducing agent) 20 mg (Part B) or rifampin (strong CYP3A inducer) 600 mg (Part C). Primary endpoints were maximum concentration (Cmax), and areas under the plasma concentration-time curve to time of last quantifiable concentration (AUC(0-t)) and extrapolated to infinite time (AUC(0-inf)). Forty-two subjects were enrolled, 14 each into Parts A, B, and C. In Part A, administration of tasurgratinib with a high-fat meal resulted in 33% reduction in Cmax and ∼23% reduction in AUC(0-t) and AUC(0-inf) of tasurgratinib, and 47% reduction in Cmax with ∼30% reduction in AUC(0-t) and AUC(0-inf) of M2. In Part B, co-administration of rabeprazole at steady state resulted in no/weak interaction with tasurgratinib (∼8% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax) and M2 (∼18% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax). In Part C, co-administration of rifampin at steady state resulted in a weak interaction with tasurgratinib (∼16% reduction in AUC(0-t) and AUC(0-inf)) and M2 (∼12% reduction in AUC(0-t) and AUC(0-inf)). Administration of tasurgratinib with a high-fat meal appeared to reduce systemic exposure of tasurgratinib, however co-administration with an acid-reducing agent or a CYP3A inducer had a minimal impact on pharmacokinetics.

Discovery of fibroblast growth factor 2-derived peptides for enhancing mice skeletal muscle satellite cell proliferation.

Skeletal muscle satellite cells (SCs) are essential for muscle regeneration. Their proliferation and differentiation are influenced by fibroblast growth factor (FGF)-2. In this study, we screened for FGF-2-derived peptides that promote SC proliferation. Utilizing photocleavable peptide array technology, a library of 7-residue peptides was synthesized, and its effect on SC proliferation was examined using a mixture of five peptides. The results showed that peptides 1-5 (136%), 21-25 (136%), 26-30 (141%), 31-35 (159%), 71-75 (135%), 76-80 (144%), and 126-130 (137%) significantly increased SC proliferation. Further experiments revealed that peptide 33, CKNGGFF, enhanced SC proliferation. Furthermore, its extended form, peptide 33-13, CKNGGFFLRIHPD, promoted SC proliferation and increased the percentage of Pax7-positive cells, indicating that SCs were maintained in an undifferentiated state. The addition of FGF-2 and peptide 33-13 further induced cell proliferation but did not increase the percentage of Pax7-positive cells. A proliferation assay using an FGF receptor (FGFR) inhibitor suggested that peptide 33-13 acts through the FGFR-mediated and other pathways. Although further research is necessary to explore the mechanisms of action of these peptides and their potential for in vivo and in vitro use, the high sequence conservation of peptides 33 and 33-13 in FGF-2 across multiple species suggests their broad application prospects in biomedical engineering and biotechnology.

Basic Fibroblast Growth Factor Supports the Function of Limbal Niche Cells via the Wnt/β-Catenin Pathway.

Purpose: To test the effects and underlying mechanisms of basic fibroblast growth factor (bFGF) on the limbal niche cell (LNC) function ex vivo. Methods: By using different concentrations of bFGF (0, 4, 8, 12, and 16 ng/mL) and fibroblast growth factor receptor (FGFR) inhibitors, the effects of bFGF on LNC proliferation, expression of stem cell markers, and transcription levels of the β-catenin were investigated. Single-cell RNA sequencing (scRNA-seq) was used to analyze the action and mechanisms of FGFR subtypes and the Wnt/β-catenin pathway during LNC culture. An mature corneal epithelial cell (MCEC)/LNC three-dimensional model was constructed to verify whether bFGF activates the Wnt/β-catenin pathway in LNC by inhibiting FGFR or β-catenin targets. Results: scRNA-seq showed that FGFR1 is the main receptor in LNC, along with the molecules in the Wnt pathway, including WNT2, FZD7, LRP5, LRP6, and β-catenin. The 12 ng/mL bFGF treatment group showed higher LNC proliferation rate and transcription levels of OCT4, SOX2, NANOG, and β-catenin than any other groups (P < 0.001). In the MCEC/LNC co-culture model, MCEC/LNC treated with 12 ng/mL bFGF promoted the aggregation of the spheres than other groups, associated with increased transcription levels of P63α, WNT2, β-catenin, and a decreased transcription level of CK12 (P < 0.001). Wnt/β-catenin inhibitor LF3 treatment reversed the abovementioned effect of bFGF. Conclusions: bFGF could maintain and promote the stemness of LNC via the FGFR1/Wnt2/FZD7/LRP6 axis in a concentration-dependent manner.