The FGF/FGFR/c-Myc axis as a promising therapeutic target in multiple myeloma.

Among blood cancers, multiple myeloma (MM) represents the second most common neoplasm and is characterized by the accumulation and proliferation of monoclonal plasma cells within the bone marrow. Despite the last few decades being characterized by the development of different therapeutic strategies against MM, at present such disease is still considered incurable. Although MM is highly heterogeneous in terms of genetic and molecular subtypes, about 67% of MM cases are associated with abnormal activity of the transcription factor c-Myc, which has so far revealed a protein extremely difficult to target. We have recently demonstrated that activation of fibroblast growth factor (FGF) signaling protects MM cells from oxidative stress-induced apoptosis by stabilizing the oncoprotein c-Myc. Accordingly, secretion of FGF ligands and autocrine activation of FGF receptors (FGFR) is observed in MM cells and FGFR3 genomic alterations represent some 15-20% MM cases and are associated with poor outcome. Thus, FGF/FGFR blockade may represent a promising strategy to indirectly target c-Myc in MM. On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.

Clinicopathological characteristics and prognosis of combined hepatocellular cholangiocarcinoma.

There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification.

FGFR Inhibition in Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain. METHODS: Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer". An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review. KEY FINDINGS AND LIMITATIONS: Somatic FGFR3 alterations are found in up to 70% of low-grade non-muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC. CONCLUSIONS AND CLINICAL IMPLICATIONS: With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.

DNA methylation-mediated FGFR1 silencing enhances NF-κB signaling: implications for asthma pathogenesis.

Background: Fibroblast growth factor receptor 1 (FGFR1) is known to play a crucial role in the pathogenesis of asthma, although the precise mechanism remains unclear. This study aims to investigate how DNA methylation-mediated silencing of FGFR1 contributes to the enhancement of NF-κB signaling, thereby influencing the progression of asthma. Methods: RT-qPCR was utilized to assess FGFR1 mRNA levels in the serum of asthma patients and BEAS-2B, HBEpiC, and PCS-301-011 cells. CCK8 assays were conducted to evaluate the impact of FGFR1 overexpression on the proliferation of BEAS-2B, PCS-301-011, and HBEpiC cells. Dual-luciferase and DNA methylation inhibition assays were performed to elucidate the underlying mechanism of FGFR1 gene in asthma. The MassARRAY technique was employed to measure the methylation levels of the FGFR1 DNA. Results: Elevated FGFR1 mRNA levels were observed in the serum of asthma patients compared to healthy controls. Overexpression of FGFR1 in BEAS-2B cells significantly enhanced cell proliferation and stimulated NF-ĸB transcriptional activity in HERK-293T cells. Furthermore, treatment with 5-Aza-CdR, a DNA demethylating agent, markedly increased the expression of FGFR1 mRNA in BEAS-2B, PCS-301-011, and HBEpiC cells. Luciferase activity analysis confirmed heightened NF-ĸB transcriptional activity in FGFR1-overexpressing BEAS-2B cells and BEAS-2B cells treated with 5-Aza-CdR. Additionally, a decrease in methylation levels in the FGFR1 DNA promoter was detected in the serum of asthma patients using the MassARRAY technique. Conclusion: Our findings reveal a potential mechanism involving FGFR1 in the progression of asthma. DNA methylation of FGFR1 inactivates the NF-ĸB signaling pathway, suggesting a promising avenue for developing effective therapeutic strategies for asthma.

Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK+ non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK+ NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication.

Chronic hearing loss turns out being a calcified chondroid mesenchymal neoplasm with FN1::FGFR2 fusion.

A 53 year old female presented with a six-year history of right-sided slow deterioration in hearing and a feeling of pressure in the right ear. The patient had not experienced any pain but reported some paresthesia of the right half of the tongue, whereas no further other cranial nerve deficits were evident. The otoscopy was unremarkable as well as the rest of the clinical ENT examination except for a slight asymptomatic swelling of the right cheek. Imaging findings showed an expansive tumor infiltrating and destroying the right lateral skull base. The tumor was partially composed of cystic/regressive lesions with high contrast media uptake. The tumor had high-signal intensity with water-sensitive sequences (T2w) and was hypointense on T1w images. We performed a tumor resection via a transparotideal-infratemporal approach. Histologically, the tumor was composed of granular variably calcified chondroid matrix with extensive regressive changes and granulation-like tissue reaction associated with calcinosis and crystal deposition. Molecular analysis of the tumor via the TruSight- RNA-Fusion panel detected a fusion involving FN1::FGFR2, consistent with "calcified chondroid mesenchymal neoplasm" (CCMN), a rare tumor entity recently defined by Liu et al 2021. In regular follow-up care no residual tumor has been detected in imaging studies (MRI and CT) within 2 years and 4 months. The biology and consequently the radio sensitivity cannot be defined precisely since long term results are missing due to the first description of this entity in 2021. As a consequence, surgical resection is recommended as the treatment of choice. Thorough clinical and radiological follow-up is mandatory as local recurrences are to be expected due to the infiltrative behavior. In case of a loco regional recurrence the fusion with FGFR2 may represent a therapeutic option for a targeted therapy on molecular level.

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Plain language summary: an analysis of the safety of futibatinib treatment in people with different types of cancer.

WHAT IS THIS SUMMARY ABOUT?: Researchers combined information from three separate phase 1 and 2 clinical trials, including over 400 people who had one of 33 different cancer types and who all received futibatinib in their clinical trial. This type of study is called a pooled analysis. Futibatinib is taken orally (by mouth) as a tablet and works by reducing the activity of a group of proteins called fibroblast growth factor receptors (FGFRs). FGFRs drive the growth of some cancers, especially cancer cells with changes in FGFR genes that make the proteins more active. Researchers wanted to look at how common some side effects were in people treated with futibatinib, how soon the side effects happened after taking futibatinib, and how they could be managed. Researchers also wanted to provide recommendations to other health care professionals on how to manage these side effects in people with cancer. WHAT WERE THE RESULTS?: In this analysis, the researchers focused on side effects that they had seen in previously completed trials of futibatinib. Overall, futibatinib was safe and tolerable. Most people (82%) had a high phosphate level in their blood (hyperphosphatemia), 27% had nail disorders, 27% had liver side effects (changes in liver-related laboratory tests), 19% had a sore mouth (stomatitis), 13% had hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome), 9% had a rash, 8% developed changes in the back of the eye (retinal disorders), and 4% of people developed cataracts. Most side effects were mild/moderate and reversible. The median time it took from starting treatment to experiencing a severe side effect ranged from 9 days (hyperphosphatemia) to 125 days (cataracts). Some side effects tended to occur early, while others developed later. Only 2% of people stopped taking futibatinib due to treatment-related side effects, and futibatinib caused no deaths. WHAT DO THE RESULTS MEAN?: The side effects from taking futibatinib were manageable and similar in people with different types of cancer. To fully understand the safety of futibatinib, researchers will need to look at what side effects are reported in people taking futibatinib over a longer time in the real-world setting (outside of clinical trials).

Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets.

Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.

Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors.

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.

Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer.

Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

FGFR3::TACC3 fusions in head and neck carcinomas: a study of nine cases highlighting phenotypic heterogeneity, frequent HPV association, and a morphologically distinct subset in favor of a putative entity.

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

Targeting the RAS/MAPK pathway in children with glioma.

PURPOSE: Pediatric gliomas are the most common brain tumor in children, encompassing both low-grade glioma (pLGG) and high-grade glioma (pHGG). Alterations in the RAS/MAPK pathway are the driver event in the majority of pLGG and account for a subset of pHGG. Identification of these alterations has resulted in the transition to targeted therapy as a treatment option. RESULTS: In pLGG, multiple trials have demonstrated superior outcomes using targeted therapy compared to traditional chemotherapy regimens. This has transformed care for these patients over the past decade with targeted therapy moving into front-line treatment regimens in certain scenarios. Despite these advances, novel targeted therapy approaches continue to present unique challenges to patient care, including optimal duration of therapy, distinct toxicity profiles and the unknown potential impact on the natural history of disease. While targeted therapy has revolutionized treatment of pLGG, additional questions remain in regard to pHGG including the role of targeted therapy in combination with other treatments, such as chemotherapy/radiation, and mechanisms of resistance. These developments are promising treatment options for pediatrics gliomas, enabling a move towards precision medicine. CONCLUSION: Herein, we review the role of RAS/MAPK targeted therapy for treatment of pediatric glioma along with the current controversies and outstanding questions.

Immunohistochemical Expression of p53 and FGFR3 Predicts Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

Locally advanced or metastatic urothelial carcinoma is a genomically and molecularly heterogeneous disease associated with various clinical outcomes. We aimed to evaluate the association between the status of p53/FGFR3 expression and the efficacy of enfortumab vedotin (EV) in metastatic urothelial carcinoma. We evaluated the association between p53 (abnormal vs. wild-type) or FGFR3 (high vs. low) expression determined by immunohistochemistry and response to EV in 28 patients with metastatic urothelial carcinoma. Overall, 60.7% showed abnormal p53, and 17.9% had high FGFR3 expression. The rates of objective response to EV were statistically higher in patients with abnormal p53 than in those with wild-type p53 (p = 0.038). Patients with pure urothelial carcinoma (n = 18) and low FGFR3 showed significantly better response to EV than those with high FGFR3. When the statuses of p53 and FGFR3 were combined, abnormal p53/low FGFR3 (vs. wild-type p53/high FGFR3) was strongly associated with favorable outcomes in both the entire cohort (p = 0.002) and in cases of pure urothelial carcinoma only (p = 0.023). Immunohistochemically abnormal p53 tumors were found to respond well to EV, while high FGFR3 tumors had a poorer response. Thus, p53 and FGFR3 are potential biomarkers for predicting response to EV treatment in patients with urothelial carcinoma.

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.

Case report: a case of lung squamous cell carcinoma with a novel FGFR3-IER5L fusion mutation responding to anlotinib.

Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene mutations in LUSC is relatively lower and treatment options for LUSC patients are very limited. We described a LUSC patient with a novel FGFR3-IER5L fusion revealed by next generation sequencing in this report. The patient refused surgery, radiotherapy or chemotherapy and received anlotinib treatment. Anlotinib is a small molecular multi-target tyrosine kinase inhibitor, which can inhibit the activity of kinases including vascular endothelial growth factor receptor 2/3 (VEGFR2/3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor α/ß (PDGFRα/ß), and c-Kit. The patient achieved partial response and the progression-free survival was 3.8 months.

The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrin ß1/TGFß signaling.

Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin ß1 plays a pivotal role in promoting EndMT by facilitating TGFß/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin ß1/TGFß signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFß1. Second, KLX suppressed TGFß/Smad signaling by inactivating integrin ß1 and inhibiting the polymerization of TGFßR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin ß1 inactivation by displacing Talin from its ß-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin ß1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.

FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand. To determine whether FGF23/FGFR4 contributes to physiologic cardiac hypertrophy, we studied FGFR4 knockout mice (FGFR4-/-) during late pregnancy. In comparison to virgin littermates, pregnant wild-type and FGFR4-/- mice showed increases in serum FGF23 levels and heart weight; however, the elevation in myocyte area observed in pregnant wild-type mice was abrogated in pregnant FGFR4-/- mice. This outcome was supported by treatments of cultured cardiac myocytes with serum from fed Burmese pythons, another model of physiologic hypertrophy, where the co-treatment with an FGFR4-specific inhibitor abrogated the serum-induced increase in cell area. Interestingly, we found that in pregnant mice, the heart, and not the bone, shows elevated FGF23 expression, and that increases in serum FGF23 are not accompanied by changes in phosphate metabolism. Our study suggests that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to hypertrophic growth of cardiac myocytes in a paracrine and FGFR4-dependent manner, and that the kidney does not respond to heart-derived FGF23.

Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress.

Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.

SLMAP3 is crucial for organogenesis through mechanisms involving primary cilia formation.

SLMAP3 is a constituent of the centrosome and is known to assemble with the striatin-interacting phosphatase and kinase (STRIPAK) complex, where it has been reported to repress Hippo signalling. The global knockout of SLMAP3 in mice results in embryonic/perinatal lethality and stunted growth without changes in the phosphorylation status of YAP. Diverse phenotypes present in the SLMAP3-/- embryos include reduced body axis, small and abnormal organs resembling defects in planar cell polarity (PCP) signalling, while also displaying the notable polycystic kidneys, a known manifestation of ciliopathies. Analysis of cell polarity in primary mouse embryonic fibroblasts (MEFs) including cell migration, orientation and mitotic spindle angle did not reveal any changes due to SLMAP3 loss in these cells, although the expression of DVL3 was significantly reduced. Furthermore, MEFs lacking FGFR1OP2 or STRN3, two other STRIPAK members, did not reveal any significant changes in any of these parameters either. Significant changes in the number of ciliated cells and primary cilium length in SLMAP3 and FGFR1OP2 deficient MEFs were evident, while a reduced primary cilium length was notable in chondrocytes of SLMAP3 deficient embryos. Our findings suggest that SLMAP3 is essential for mouse embryogenesis through novel mechanisms involving the primary cilium/PCP and protein stability independent of Hippo signalling.