Fibroblast Growth Factor Receptor Research Articles

OR02-06 FGFR2 Mediates Zona Glomerulosa Morphogenesis, Aldosterone Secretion And Β-Catenin-induced Adrenal Hyperplasia

Abstract Disclosure: V. Chortis: None. K. Dulanjalee: None. N.A. Guagliardo: None. M.S. Shah: None. R. Claudio: None. P.Q. Barrett: None. K.S. Borges: None. D.L. Carlone: None. D.T. Breault: None. Fibroblast Growth Factor Receptors (FGFRs) are tyrosine kinase receptors with critical roles in organogenesis and tissue homeostasis. We have recently shown that Fgfr2 deletion in the outermost zone of the mouse adrenal cortex (zona Glomerulosa, zG) during post-natal development leads to disordered morphology. Interestingly, Fgfr2 is up-regulated in the zG of mice with adrenal hyperplasia due to constitutive activation of Wnt/beta-catenin signaling. Here, we seek to delineate the role of FGFR2 in adrenal morphology and function during postnatal development, adulthood homeostasis, as well as during β-catenin-induced adrenal hyperplasia. To address this, we used i) a mouse model of conditional Fgfr2 loss (Fgfr2-cKO), in which zG-specific Fgfr2 deletion begins during early post-natal development, and ii) an inducible mouse model (Fgfr2-icKO), in which Fgfr2 deletion in the zG during adult life is tamoxifen-dependent. Fgfr2 loss in Fgfr2-cKO mice disrupted zG cell differentiation in steroidogenically mature cells and limited their capacity to proliferate and undergo trans-differentiation into the adjacent zona Fasciculata. zG cell de-differentiation was also evident upon acute loss of Fgfr2 in adult Fgfr2-icKO mice. Furthermore, Fgfr2 loss in a mouse model of beta-catenin-induced zG hyperplasia was sufficient to fully abrogate adrenal hyperplasia. Treatment with pan-FGFR small molecule inhibitors suppressed cellular proliferation in the mouse zG and inhibited aldosterone secretion. Taken together, these results suggest FGFR2 has a critical role in normal adrenal development and tissue homeostasis and is an essential mediator of beta-catenin-induced adrenal hyperplasia. FGFR2 targeting may be meaningful in patients with conditions associated with aldosterone excess. Presentation: Thursday, June 15, 2023

Pemigatinib for Cholangiocarcinoma– A Novel Drug

Cholangiocarcinoma(CLCA) is a cancer that develops in the narrow tubes known as bile ducts, which transport the digesting fluid bile. This disease, also recognized as Hepatic-duct cancer, is a form of tumor that is extremely difficult to cure with standard chemotherapy. iCLCA refers to cancers that develop within the gastrointestinal tract of the Hepatic-ducts inside the liver and are usually instigated by mutations in the Fibroblast Growth Factor Receptor2 (FiGFR2) gene. Pemigatinib(Pg) is a distinctive, powerful medication that specifically inhibits the action of mutated FGFR2 and is now identified being a viable therapy option for individuals with intrahepatic CLCA. Cholangiocarcinoma (CLCA) is a diverse category of cancers with few therapeutic options. Considering the latest developments in health oncology, CLCA individuals with metastasizing cancer have a terrible prognosis, with an overall median lifespan of barely an entire year. The CLCA health community has made substantial efforts in the recent decade to enhance distinct clinical results by introducing molecularly embattled treatments in this environment. Among some of these therapies, the FiGFR 2 inhibitor Pg has been granted rapid authorization by the USA-Food and Drug Administration (FDA) in CLCA individuals who have FiGFR2 gene combinations or additional rearrangements founded on the outcomes of the FIGHT-202 trial, making it the initial molecularly specific rehabilitation to be endorsed as a remedy of CLCA.This review seeks to present a concise review of pemigatinib's latest advancement, with a precise emphasis on the FIGHT-202 study, the endorsement of this FiGFR inhibitor, and the impending problems related to the routine of FiGFR-directed medicines in CLCA individuals.

Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial

Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis. HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing. Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred. Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. Akero Therapeutics.

2398P Are fibroblast growth factor receptor 3 (FGFR3) alterations a possible predictive factor for platinum-based chemotherapy and immunotherapy in metastatic urothelial carcinoma (MUC)?

2398P Are fibroblast growth factor receptor 3 (FGFR3) alterations a possible predictive factor for platinum-based chemotherapy and immunotherapy in metastatic urothelial carcinoma (MUC)?

124P Clinicopathological nomogram for predicting fibroblast growth factor receptor 2 (FGFR2) gene fusion/rearrangement (F/R) in intrahepatic cholangiocarcinoma (iCCA)

124P Clinicopathological nomogram for predicting fibroblast growth factor receptor 2 (FGFR2) gene fusion/rearrangement (F/R) in intrahepatic cholangiocarcinoma (iCCA)

95MO Tinengotinib in patients with advanced, fibroblast growth factor receptor (FGFR) inhibitor refractory/relapsed cholangiocarcinoma

95MO Tinengotinib in patients with advanced, fibroblast growth factor receptor (FGFR) inhibitor refractory/relapsed cholangiocarcinoma

EP11.21: Prenatal diagnosis of hypochondroplasia due to de novo fibroblast growth factor receptor 3 loss

EP11.21: Prenatal diagnosis of hypochondroplasia due to <i>de novo</i> fibroblast growth factor receptor 3 loss

192P Impact of oncogenic fibroblast growth factor receptor (FGFR) alterations in patients with advanced solid tumors in a real-world setting

192P Impact of oncogenic fibroblast growth factor receptor (FGFR) alterations in patients with advanced solid tumors in a real-world setting

1012P First-in-human study of ABSK-011, a novel, highly selective fibroblast growth factor receptor (FGFR) 4 inhibitor for treating advanced hepatocellular carcinoma (HCC) with FGF19 overexpression

1012P First-in-human study of ABSK-011, a novel, highly selective fibroblast growth factor receptor (FGFR) 4 inhibitor for treating advanced hepatocellular carcinoma (HCC) with FGF19 overexpression

230P Fibroblast growth factor receptor (FGFR) co-alteration (co-alt) landscape and its impact on erdafitinib (erda) response in the phase II open-label, single-arm RAGNAR trial

230P Fibroblast growth factor receptor (FGFR) co-alteration (co-alt) landscape and its impact on erdafitinib (erda) response in the phase II open-label, single-arm RAGNAR trial

The Effects of Fibroblast Growth Factor-2 (FGF-2) on Achilles Tendon Injury

Category: Basic Sciences/Biologics; Ankle Introduction/Purpose: Achilles tendon defects are a challenging problem, and there is a need for new treatments. We investigated the use of Platelet-rich fibrin (PRF), a dense fibrin scaffold containing many growth factors and cytokines, for Achilles tendon injuries. The study found that PRF accelerates healing by promoting the proliferation and activation of tenocytes via FGF receptor/AKT signaling and TGF-β/SMAD3 signaling. While FGF-2, a growth factor in PRF, has been shown to promote tenocyte differentiation and proliferation, its effect on Achilles tendon injuries has not been reported. Therefore, this study aimed to investigate the effect of FGF-2 on Achilles tendon healing when administered alone and to determine its specific contribution to the healing process. Methods: We used a rat model of Achilles tendon defect. A 4-mm portion of the right Achilles tendon, 4 mm proximal to the calcaneal insertion, was resected to create a tendon defect. Gelatin hydrogel sheet (MedGel PI5) as a scaffold for PBS, FGF-2 (Rigroth®), and FGF receptor inhibitor (FGFRI: Pemigatinib) was placed into the gap before suturing it with nylon sutures. We observed HE-stained specimens at 200x and assessed histological healing by counting cells and vessels and grading cell morphology. The motor function was evaluated by the Basso, Beattie, and Bresnahan (BBB) score and the treadmill test. We compared the effects of FGF-2 on tenocytes isolated from rat Achilles tendons in the control, FGF2, and FGFRI groups. The proliferation and migration of tenocytes were measured by MTS assay and wound closure assay, respectively. Protein expression, such as Tenomodulin (Tnmd), Collagen Ⅰ, Ⅲ, and Screlaxis-A in cells, were evaluated by Western Blotting. Results: In the rat model, the number of cells, vessels and cell morphology scores at the defect sites increased in the FGF-2 group and decreased in the FGFRI group at 2 and 4 weeks postoperatively. In the motor functional evaluation, the FGF-2 group showed earlier improvement in the BBB score and the treadmill test compared to the control and FGFRI groups. The MTS assay showed that the number of viable cells was higher in the FGF-2 group and lower in the FGFRI group than in the control. Wound closure assay showed tenocyte migration was increased in the FGF-2 group and decreased in the FGFRI group. Regarding protein expression, Tnmd, Collagen I, III, and Screlaxis-A were increased in the FGF-2 group and decreased in the FGFRI group. Conclusion: In vivo, FGF-2 promoted healing of Achilles tendon injury, and FGFRI impeded it in terms of motor function and histology. Additionally, in vitro, FGF-2 promoted the proliferation and migration of tenocytes and enhanced extracellular matrix production, while FGFRI diminished these effects. Although native FGF-2 is produced at the injured site, further administration of FGF-2 accelerated Achilles tendon injury healing, while inhibiting the FGF receptor delayed recovery in this study. Therefore, FGF- 2 is very important in Achilles tendon injury healing and may promote recovery by enhancing angiogenesis, proliferation, and extracellular matrix production of tenocytes.

1621P Efficacy and safety of erdafitinib in adults with pancreatic cancer and prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase II open-label: Single-arm RAGNAR trial

1621P Efficacy and safety of erdafitinib in adults with pancreatic cancer and prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase II open-label: Single-arm RAGNAR trial

2359O Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt)

2359O Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt)

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

Structural asymmetry in FGF23 signaling

Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor (FGFR), α-Klotho, and heparin sulfate. These structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling.

FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation.

Fibroblast growth factor receptor 3 (FGFR3) alterations are common in patients with bladder cancer (BCa). While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for FGFR3-altered (aFGFR3) BCa patients, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 BCa and demonstrated that mutant FGFR3 indirectly induces a "cold" TME in mouse BCa models. Single-cell RNA sequencing (scRNA-seq) revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T cell recruitment and antigen presentation capabilities. Increased serine synthesis in BCa cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy.

Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive Tcell treatment for RMS. The 3A11 CAR Tcells induced robust cytokine production and cytotoxicity against RMS cell lines invitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR Tcells, confirming the selectivity of 3A11 CAR Tcells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR Tcells are persistent invivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR Tcell therapy targeting FGFR4 to treat patients with RMS.

Targeting FGFR Pathways in Gastrointestinal Cancers: New Frontiers of Treatment.

In carcinogenesis of the gastrointestinal (GI) tract, the deregulation of fibroblast growth factor receptor (FGFR) signaling plays a critical role. The aberrant activity of this pathway is described in approximately 10% of gastric cancers and its frequency increases in intrahepatic cholangiocarcinomas (iCCAs), with an estimated frequency of 10-16%. Several selective FGFR inhibitors have been developed in the last few years with promising results. For example, targeting the FGFR pathway is now a fundamental part of clinical practice when treating iCCA and many clinical trials are ongoing to test the safety and efficacy of anti-FGFR agents in gastric, colon and pancreatic cancer, with variable results. However, the response rates of anti-FGFR drugs are modest and resistances emerge rapidly, limiting their efficacy and causing disease progression. In this review, we aim to explore the landscape of anti-FGFR inhibitors in relation to GI cancer, with particular focus on selective FGFR inhibitors and drug combinations that may lead to overcoming resistance mechanisms and drug-induced toxicities.

FGF21 protects against doxorubicin-induced cardiotoxicity by inhibiting connexin 43 ubiquitination

BackgroundFibroblast growth factor 21 (FGF21) regulates glycolipid metabolism and insulin homeostasis and acts as a cardioprotective factor by protecting against myocardial ischemia/reperfusion injury, hypertension, and vascular dysfunction. FGF21 has been reported to prevent Doxorubicin (Dox)-induced cardiotoxicity, and the related signaling pathway is worthy of further study. Connexin43 (Cx43) protein was reduced by Dox treatment, especially low phosphorylated form of Cx43. Thus the aim of study is to explore the protection effect of FGF21 on Dox induced cardiotoxicity by improving the expression of Cx43 and the involved signaling pathway. Methods and resultsFGF21 inhibited apoptosis in Dox-treated mice and cardiomyocytes. FGF21 increased the levels of connexin43 phosphorylated at serine (S) 282 (p-Cx43 S282) and total Cx43 to inhibit Dox-induced apoptosis. By RNA sequencing, we found that deubiquitinase monocyte chemoattractant protein-induced protein 1 (MCPIP1) expression was increased by FGF21. We further found that FGF21 induced the phosphorylation of fibroblast growth factor receptor 1 (FGFR1), extracellular signal-regulated kinase 1 and 2 (Erk1/2), and Elk. Phosphorylated Elk translocated to the nucleus and increased the expression of MCPIP1. Then, MCPIP1 bound neural precursor cell expressed developmentally downregulated protein 4 (Nedd4), an E3 ubiquitination ligase, as shown by co-immunoprecipitation (Co-IP), and suppressed Cx43 ubiquitination and degradation, competitively inhibiting the binding of Cx43 with Nedd4. Thus Nedd4 could not bind and ubiquitinate Cx43, leading to the up-regulation of Cx43 and phosphorylation of Cx43 at S282. ConclusionsFGF21 inhibited the effects of Dox on cardiomyocytes by elevating the phosphorylation of Cx43 at S282 and total Cx43 expression. This study suggests a previously unknown mechanism for the FGF21-mediated enhancement of cardiomyocyte survival and provides an effective approach to protect against the adverse cardiac effects of Dox.

Role of Fibroblast Growth Factor Receptor 2 (FGFR2) in Corneal Stromal Thinning.

To determine the role of fibroblast growth factor receptor 2 (FGFR2)-mediated signaling in keratocytes during corneal development, a keratocyte-specific FGFR2-knockout (named FGFR2cKO) mouse model was generated, and its phenotypic characteristics were determined. A FGFR2cKO mouse model was generated by the following method: FGFR2 flox mice were crossed with the inducible keratocyte specific-Cre mice (Kera-rtTA/tet-O-Cre). Both male and female FGFR2cKO- and control mice (1 to 3-months-old) were analyzed for changes in corneal topography and pachymetry maps using the optical coherence tomography (OCT) method. The comparative TUNEL assay and immunohistochemical analyses were performed using corneas of FGFR2cKO and control mice to determine apoptotic cells, and expression of collagen-1 and fibronectin. Transmission electron microscopic analysis was conducted to determine collagen structures and their diameters in corneas of FGFR2cKO and control mice. OCT-analyses of corneas of FGFR2cKO mice (n = 24) showed localized central thinning and an increased corneal steepness compared to control mice (n = 23). FGFR2cKO mice further showed a decreased expression in collagen-1, decreased collagen diameters, acute corneal hydrops, an increased fibronectin expression, and an increased number of TUNEL-positive cells suggesting altered collagen structures and keratocytes' apoptosis in the corneas of FGFR2cKO mice compared to control mice. The FGFR2cKO mice showed several corneal phenotypes (as described above in the results) that are also exhibited by the human keratoconus corneas. The results suggested that the FGFR2cKO mouse model serves to elucidate not only the yet unknown role of FGFR2-mediated signaling in corneal physiology but also serves as a model to determine molecular mechanism of human keratoconus development.