Mutations In Fibroblast Growth Factor Receptor Research Articles

Abstract A024: Genomic peroxisome proliferator-activated receptor gamma (PPARG) study: A sponsored testing program to identify patients harboring genetic alterations in advanced UC in support of the FX-909 Phase 1 study

Abstract The transcription factor PPARG is associated with the luminal lineage subtype representing ~65% of advanced urothelial cancer (UC) patients. Recurrent genetic alterations in PPARG, fibroblast growth factor receptor 3 (FGFR3), and the heterodimeric binding partner for PPARG, retinoid X receptor alpha (RXRA), are characteristic of this luminal subtype. FX-909, a covalent PPARG inverse agonist, represents a promising first-in-class therapy for patients with advanced UC. FX-909-CLINPRO-1 [NCT05929235] is an open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, biologic activity, and preliminary clinical activity of FX-909. This study includes a Phase 1b expansion cohort, which will enroll advanced UC patients with genetic alterations in PPARG, RXRA, and/or FGFR3. FlareTx is sponsoring a testing program called Genomic PPARG Study (GPS) to enable investigators to identify patients with these relevant genetic alterations. Tumors collected from patients with advanced UC were sequenced using the Tempus xT assay (DNA-seq of 648 genes at 500x coverage; RNA-seq). A clinical report is generated and returned to the physician to guide selection of approved therapies, and if appropriate to support eligibility for inclusion in the study. FlareTx is provided with de-identified genomic data, where assessment of the prevalence of genetic alternations such as copy number variation (CNV), fusions and mutations (single nucleotide variants) in PPARG, RXRA and FGFR3 are undertaken. Additionally, luminal molecular classification is performed using the Robertson method [1]. PPARG mean expression value are normalized by transcripts-per-million (TPM) and reported as Log2[TPM+1]. In the initial data set of 27 patients, 3 patients had PPARG amplification (CN >/= 3), 3 patients had RXRA hotspot mutation (S427F) [2], 6 patients had FGFR3 mutation(s), and 1 patient had both PPARG amplification and a FGFR3 mutation. Twenty of 27 patients tested had sufficient starting material of good quality to also perform whole transcriptome analysis. The mean mRNA expression level of PPARG was 6.77 Log2[TPM+1] (range 2.91 Log2[TPM+1] – 9.22 Log2[TPM+1]). Consistent with the Robertson subtype distribution, 65% of patients were luminal and 35% were non-luminal (basal-squamous and neuronal); 10 of 13 luminal patients had one or more genetic alteration in PPARG, RXRA and/or FGFR3. High PPARG expression was associated with luminal subtype compared to non-luminal subtype (7.90 Log2[TPM+1] vs 4.67 Log2[TPM+1]; p=0.00042). GPS is open at two active Phase 1 sites, with several more planned as the study advances towards the Phase 1B dose expansion stage. GPS runs concurrently with the FX-909 study and is a novel precision strategy to maximize identifying advanced UC patients with actionable genetic alterations to potentially enroll in the clinical study.

The combination of gemcitabine plus an anti-FGFR inhibitor can have a synergistic antitumor effect on FGF-activating cholangiocarcinoma.

Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50=19.3, 22.6 mg/dl, p=0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50=7.18,7.60nM, p=0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.

Construction of a Lentiviral Vector for Fgfr2 Overexpression and its Impact on the Biological Behavior of Cranial Suture Mesenchymal Stem Cells.

Suture mesenchymal stem cells (SuSCs), possessing self-renewal and multilineage differentiation abilities, play a crucial role in cranial bone growth. However, the impact of the disease-causing fibroblast growth factor receptor 2 (FGFR2) mutation on SuSCs in Crouzon syndrome has not been explored. This study aims to employ a lentivirus to overexpress Fgfr2 and investigate its role in the pathogenesis of Crouzon syndrome. Starting with the prevalent FGFR2 mutation site in patients with Crouzon syndrome, a lentiviral vector carrying the Fgfr2.C361Y mutation was developed and transfected into SuSCs, with a determined multiplicity of infection values. The experimental group, SuSCs+Fgfr2.C361Y, was compared with the empty vector and normal SuSC groups. Cell proliferation, cycle, apoptosis, and osteogenic functionality were assessed using CCK-8 assays, flow cytometry, ALP activity assays, and real-time quantitative polymerase chain reaction. The lentiviral vector effectively infected SuSCs, leading to heightened Fgfr2 expression, with optimal multiplicity of infection values of 80. The experimental group demonstrated decreased proliferation activity and a higher apoptosis rate compared with controls (P < 0.05). After osteogenic induction, the experimental group showed significantly higher ALP activity than controls (P < 0.05). Real-time quantitative polymerase chain reaction indicated lower mRNA expression levels of Gli1, Axin2, Pcna, Cdk2, and Bcl-2 in the experimental group than controls, whereas Bax, Runx2, and Bmp-2 showed higher expression (P < 0.05). This study constructed a lentivirus vector to upregulate Fgfr2 expression in SuSCs, suppressing stem cell stemness by inhibiting proliferation, promoting apoptosis, and accelerating premature osteogenic differentiation, resulting in premature suture closure. These findings establish the groundwork for further understanding the pathogenesis of Crouzon syndrome.

Abstract LB162: Tinengotinib in patients with advanced solid tumors harboring actionable FGFR1-3 mutations

Abstract Background: Fibroblast growth factor receptor (FGFR) alterations occur across various malignancies and are potent oncogenic drivers in multiple tumor types. FGFR inhibitors have demonstrated efficacy in several cancers with FGFR alterations. Tinengotinib is a novel kinase inhibitor with high potency to a variety of FGFR 1/2/3 kinase domain mutations and has shown promising efficacy in several ongoing clinical studies. Here, we present pooled data of tinengotinib in previously treated solid tumor patients (pts) with actionable FGFR1-3 mutations from four trials (NCT03654547, NCT04742959, NCT04919642, NCT05253053). Methods: Eligible pts received tinengotinib orally once daily (daily dose ranging from 5-12mg) until disease progression. Analyses of best overall response (BOR) rate, disease control rate (DCR), median progression-free survival (mPFS), median duration of response (mDOR) and treatment-related adverse events (TRAEs) were performed. Results: As of 3-Aug-2023, 53 solid tumor pts with actionable FGFR1-3 mutations were enrolled between Dec-2019 to Aug-2023 in the US and China. The median follow-up time was 14.5 (range, 3.3-43.8) months. Median age was 58 years (range, 29-83). Most pts were female (62%), had ECOG of 1 (68%) and were heavily pretreated with 55% having ≥3 lines of prior antitumor therapy. The most frequent FGFR mutation enrolled was in FGFR2 (77%) followed by FGFR1 (19%) and FGFR3 (11%). 25 pts (47%) had received prior therapy with FGFR inhibitor. A total of 45 pts were efficacy-evaluable, including cholangiocarcinoma (CCA, n=25), colon cancer (n=5), breast cancer (n=3), prostate cancer (n=3), head and neck cancer (n=3), urothelial cancer (n=3), pancreatic cancer (n=1), gastric cancer (n=1) and leiomyosarcoma (n=1). mPFS reached 6.83 (95% CI, 4.90-8.34) months. Partial responses were observed in 16/45 (35.6%) pts across 6 distinct tumor types, including CCA, breast, prostate, urothelium, colon and head and neck cancer. mDOR was 6.74 (95% CI, 3.52-9.46) months. For 44 pts with measurable target lesions per RECISTv1.1, the BOR rate and DCR were 36.4% and 86.4%, respectively. For 22 pts with prior FGFR inhibitor, mPFS was 5.98 (95% CI, 3.75-9.10) months and their BOR rate and DCR were 40.9% and 86.4%. TRAEs were reported in 46 (86.8%) pts, with 13 (24.5%) Grade (G) 1-2, 30 (56.6%) G3, 2 (3.8%) G4, and no G5. The most common TRAEs (≥20%) were hypertension, stomatitis, diarrhea, nausea, blood thyroid stimulating hormone increased, fatigue and anemia. Side effects were manageable and reversible with dose hold and/or dose reduction. Conclusions: We observed promising clinical benefit with tinengotinib in heavily pretreated solid tumor pts with FGFR1-3 mutations. The side effects profile was manageable and no new safety signals have been identified. Further research is planned to evaluate the safety and efficacy of tinengotinib in pts with FGFR1-3 mutations across a wider variety of tumor types. Citation Format: Sarina A. Piha-Paul, Chih-Yi "Andy" Liao, Lionel Fonkoua, Amit MahipaI, Sanjay Goel, Christos Fountzilas, Lin Shen, Daneng Li, Dustin Deming, Farshid Dayyani, Weiqing Han, Zuoxing Niu, Jean Fan, Peng Peng, Hui Wang, Peng Huang, Frank Wu, Milind Javle. Tinengotinib in patients with advanced solid tumors harboring actionable FGFR1-3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB162.

FGFR3 Mutations in Urothelial Carcinoma: A Single-Center Study Using Next-Generation Sequencing.

Background: Mutations of fibroblast growth factor receptor 3 (FGFR3) are associated with urothelial carcinoma (UC) oncogenesis and are considered an important therapeutic target. Therefore, we evaluated the FGFR3 mutation rate and its clinical significance in urothelial carcinoma (UC) using next-generation sequencing. Methods: A total of 123 patients with UC who were treated at Chonnam National University Hospital (Gwang-ju, Korea) from January 2018 to December 2020 were enrolled. We performed NGS using the Oncomine panel with tumor specimens and blood samples corresponding to each specimen. We analyzed the FGFR3 mutation results according to the type of UC and the effects on early recurrence and progression. Results: The mean age of the patients was 71.39 ± 9.33 years, and 103 patients (83.7%) were male. Overall, the FGFR3 mutation rate was 30.1% (37 patients). The FGFR3 mutation rate was the highest in the non-muscle-invasive bladder cancer (NMIBC) group (45.1%), followed by the muscle-invasive bladder cancer (22.7%) and upper tract UC (UTUC) (14.3%) groups. Patients with FGFR3 mutations had a significantly lower disease stage (p = 0.019) but a high-risk of NMIBC (p < 0.001). Conclusions: Our results revealed that FGFR3 mutations were more prevalent in patients with NMIBC and lower stage UC and associated with a high-risk of NMIBC. Large multicenter studies are needed to clarify the clinical significance of FGFR3 mutations in UC.

Pilocytic astrocytoma: The paradigmatic entity in low‑grade gliomas (Review).

Among low-grade gliomas, representing 10-20% of all primary brain tumours, the paradigmatic entity is constituted by pilocytic astrocytoma (PA), considered a grade 1 tumour by the World Health Organization. Generally, this tumour requires surgical treatment with an infrequent progression towards malignant gliomas. The present review focuses on clinicopathological characteristics, and reports imaging, neurosurgical and molecular features using a multidisciplinary approach. Macroscopically, PA is a slow-growing soft grey tissue, characteristically presenting in association with a cyst and forming a small mural nodule, typically located in the cerebellum, but sometimes occurring in the spinal cord, basal ganglia or cerebral hemisphere. Microscopically, it may appear as densely fibrillated areas composed of elongated pilocytic cells with bipolar 'hairlike' processes or densely fibrillated areas composed of elongated pilocytic cells with Rosenthal fibres alternating with loosely fibrillated areas with a varied degree of myxoid component. A wide range of molecular alterations have been encountered in PA, mostly affecting the MAPK signalling pathway. In detail, the most frequent alteration is a rearrangement of the BRAF gene, although other alterations include neurofibromatosis type-1 mutations, BRAFV600E mutations, KRAS mutations, fibroblast growth factor receptor-1 mutations of fusions, neurotrophic receptor tyrosine kinase family receptor tyrosine kinase fusions and RAF1 gene fusions. The gold standard of PA treatment is surgical excision with complete margin resection, achieving minimal neurological damage. Conventional radiotherapy is not required; the more appropriate treatment appears to be serial follow-up. Chemotherapy should only be applied in younger children to avoid the risk of long-term growth and developmental issues associated with radiation. Finally, if PA recurs, a new surgical approach should be performed. At present, novel therapy involving agents targeting MAPK signalling pathway dysregulation is in development, defining BRAF and MEK inhibitors as target therapeutical agents.

Clinical manifestations and spermatogenesis outcomes in Chinese patients with congenital hypogonadotropic hypogonadism caused by inherited or de novo FGFR1 mutations.

Fibroblast growth factor receptor 1 (FGFR1) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l-1, follicle-stimulating hormone (FSH) levels were 1.0 IU l-1, and testosterone levels were 1.3 nmol l-1. In contrast, the de novo group had LH levels of 0.2 IU l-1, FSH levels of 0.5 IU l-1, and testosterone levels of 0.9 nmol l-1, indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

Promising horizons in achondroplasia along with the development of new drugs.

Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.

Molecular features of gastrointestinal stromal tumors “wild-type” (&lt;i&gt;KIT/PDGFRA&lt;/i&gt; WT)

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Their main features are the expression of CD117 (KIT) and mutations of KIT or PDGFRA in 85 % of patients. however, 10–15 % of adult GIST and 85 % of pediatric GIST do not have KIT/PDGFRA mutations (KIT/PDGFRA WT GIST or “wild-type” GIST). The prognosis and clinical course of these tumors and GIST with KIT/PDGFRA mutations differ. “Wild-type” GIST are quite heterogeneous group of tumors in terms of clinical phenotype, genetic etiology, and molecular pathways. Gastrointestinal stromal tumors are divided into SDH-deficient and SDH-competent based on the succinate dehydrogenase (SDH) complex. SDH-deficient GIST occur predominantly in children and young patients with Carney–Stratakis syndrome and Carney triad; there are also sporadic tumors. More than half of SDH-deficient GIST contain mutations in SDHA, SDHB, SDHD or SDHC, while the rest are caused by hypermethylation of the SDHC promoter. SDH-competent “wild-type” GIST include tumors with BRAF, RAS, or NF1 mutations that activate the RAS-RAF-MAPK pathway and KIT/PDGFRA/SDH/RAS-P WT GIST subtype or “quadruple wild type” GIST. The genomic profiles of these tumors and GIST with KIT/PDGFRA mutation or SDH deficiency differ significantly. One of the features of “quadruple wild type” GIST is activation of the FGFR (fibroblast growth factor receptors) signaling pathway due to chimeric FGFR, FGFR mutations, or overexpression of FGF (fibroblast growth factor). Another feature is chimeric genes containing fragments of NTRK, BRAF, FGFR and other genes that behave as oncogene drivers. In “quadruple wild-type” GIST the somatic mutations in TP53, MAX, MEN1, CTNND2, CHD4, ARIDIA and other genes were revealed as well as in the cell cycle genes RB1, CDK4, CDKN1B. There is no specific treatment for patients with “wild-type” GIST; the choice of drug is determined by the genetic disorder. There is a need to improve our understanding of the molecular mechanisms underlying the different GIST subtypes to develop more effective therapeutic approaches.

Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201

Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 260 patients were enrolled and treated (A-CD, n= 101; A-ID, n= 103; B, n= 44; unconfirmed FGF/FGFR status, n= 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n= 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n= 3; V553M, n= 1; N540K/S, n= 2; M528I, n= 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

Unraveling the Complexity of Apert Syndrome: Genetics, Clinical Insights, and Future Frontiers.

Apert syndrome (AS), also known as type I acrocephalosyndactyly, is a rare congenital condition characterized by craniosynostosis resulting from missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. This comprehensive review delves into AS, covering its clinical manifestations, genetics, diagnosis, medical management, psychosocial considerations, and future research directions. AS presents with distinct features, including a brachycephalic skull, midface hypoplasia, and limb anomalies such as syndactyly. It follows an autosomal dominantinheritance pattern with mutations in the FGFR2 gene. Prenatal diagnosis is possible through advanced imaging techniques and molecular testing. The multidisciplinary approach to AS management involves surgical interventions, orthodontics, and psychological support. Although no curative treatment exists, early interventions can significantly improve function and aesthetics. The quality of life for AS patients is influenced by psychosocial factors, necessitating comprehensive support for both patients and their families. Future research directions include gene therapy, understanding cellular responses to FGFR2 mutations, and addressing genetic heterogeneity. Collaborative efforts are vital to advancing knowledge about AS and its genetic underpinnings. Overall, this review serves as a valuable resource for healthcare professionals, educators, and researchers, contributing to a deeper understanding of AS and facilitating advancements in diagnosis and treatment.

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.

Functional Distinctions of Endometrial Cancer-Associated Mutations in the Fibroblast Growth Factor Receptor 2 Gene.

Functional analysis of somatic mutations in tumorigenesis facilitates the development and optimization of personalized therapy for cancer patients. The fibroblast growth factor receptor 2 (FGFR2) gene is frequently mutated in endometrial cancer (EC), but the functional implications of FGFR2 mutations in cancer development remain largely unexplored. In this study, we introduced a reliable and readily deployable screening method to investigate the effects of FGFR2 mutations. We demonstrated that distinct mutations in FGFR2 can lead to differential downstream consequences, specifically affecting a disintegrin- and metalloprotease 17 (ADAM17)-dependent shedding of the epidermal growth factor receptor (EGFR) ligand heparin-binding EGF-like growth factor (HB-EGF) and phosphorylation of mitogen-activated protein kinases (MAPKs). Furthermore, we showed that the distribution of mutations within the FGFR2 gene can influence their oncogenic effects. Together, these findings provide important insights into the complex nature of FGFR2 mutations and their potential implications for EC. By unraveling the distinct effects of different mutations, our study contributes to the identification of personalized treatment strategies for patients with FGFR2-mutated cancers. This knowledge has the potential to guide the development of targeted therapies that specifically address the underlying molecular alterations associated with FGFR2 mutations, ultimately improving patient outcomes in EC and potentially other cancer types characterized by FGFR2 mutations.

Fibroblast growth factor receptor 3 mutation attenuates response to immune checkpoint blockade in metastatic urothelial carcinoma by driving immunosuppressive microenvironment

BackgroundImmune checkpoint blockade (ICB) therapy holds promise in metastatic urothelial carcinoma (UC). Fibroblast growth factor receptor 3 (FGFR3) mutation drives T-cell-depleted microenvironment in UC, which led to the hypothesis that...

Avelumab as First-Line Maintenance Treatment in Locally Advanced or Metastatic Urothelial Carcinoma.

This work provides a summary of guideline recommendations and an expert position on the use of maintenance avelumab therapy based on a review of current international clinical practice guidelines for locally advanced or metastatic urothelial carcinoma (UC). A PubMed literature search was conducted in March 2022 (updated in July 2023) to identify guidelines for locally advanced or metastatic UC. An expert panel (four oncologists and one urologist) reviewed the guidelines and clinical evidence, and discussed practical questions regarding the use of avelumab maintenance therapy in this clinical setting. The National Comprehensive Cancer Network, European Association of Urology and European Society for Medical Oncology guidelines recommend first-line cisplatin-containing chemotherapy for cisplatin-eligible patients, carboplatin-gemcitabine for cisplatin-ineligible patients who are fit for carboplatin, or immunotherapy with programmed death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) in platinum-ineligible patients. Maintenance avelumab is recommended in patients with response/stable disease following chemotherapy (regardless of PD-L1 status). In patients who relapse after/during chemotherapy, options include immunotherapy, erdafitinib [in those with fibroblast growth factor receptor (FGFR) mutations], enfortumab vedotin or further chemotherapy. The expert panel provided the following practical guidance: (1) consider maintenance avelumab in all eligible patients; (2) continue avelumab until disease progression/unacceptable toxicity; (3) ideally, administer six cycles of platinum-based chemotherapy prior to maintenance avelumab; (4) perform radiological evaluation after four chemotherapy cycles and prior to maintenance avelumab; (5) carboplatin-gemcitabine followed by maintenance avelumab is preferred in cisplatin-ineligible patients (regardless of PD-L1 expression), but consider first-line immunotherapy in PD-L1-positive patients and platinum-ineligible patients (regardless of PD-L1 status); and (6) for patients who relapse on avelumab, second-line options include enfortumab vedotin, FGFR inhibitors (in those with FGFR mutations) or clinical trial inclusion. In conclusion, avelumab maintenance therapy is recommended following platinum-based chemotherapy in all eligible patients with locally advanced or metastatic UC, continued until disease progression or unacceptable toxicity.

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations.

The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

LGG-21. FGFR1 GENE MUTATION AS A POTENTIAL RISK FACTOR FOR SPONTANEOUS INTRACRANIAL HEMORRHAGE IN PEDIATRIC LOW GRADE GLIOMA PATIENTS

Abstract The Fibroblast Growth Factor Receptor 1 (FGFR1) gene is the second most altered gene in pediatric LGGs and has been associated with poorer prognoses. A recent study suggested a link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGG patients, an event that can be detrimental to cognitive development and, in some cases, even fatal. The current study aimed to further confirm this link by following 49 pediatric LGG patients treated at the Arnold Palmer Hospital for Children from 2007-2022 and investigating the occurrences of spontaneous intracranial hemorrhage. We accessed their treatment course, clinical outcome, radiographic findings, and pathological findings. Genetic analysis was performed as part of their standard of care at the time of tumor resection or biopsy. Of the forty-nine pediatric LGG patients we followed, eight (16.3%) experienced spontaneous intracranial hemorrhage. Five of these eight patients (62.5%) had an FGFR1 mutation. Out of the forty-nine patients, only six of them had an FGFR1 mutation, and five out of the six (83.3%) experienced spontaneous intracranial hemorrhage at some point during treatment. The one patient that did not experience hemorrhage lacked a classic FGFR1 mutation and presented with a variant of unknown significance that has yet to be regarded as pathogenic. These findings are consistent with the aforementioned study and are significant because, to date, little is known about the tumor-specific risk factors for these spontaneous intracranial hemorrhages. Understanding the risk factors could help clinicians better predict these occurrences and potentially prevent their devastating effects.

Significance of the FGFR3 mutation in Chinese patients with bladder cancer.

Bladder cancer (BC) is the 10th most common malignancy worldwide. The high recurrence rates of BC lead to significant treatment challenges. With the development of molecular biology techniques, research has shown that gene abnormalities are closely related to the occurrence and development of BC. This study analyzed the detection results of gene mutations in the tissue samples of BC patients and explored the relationship between fibroblast growth factor receptor 3 (FGFR3) and the prognosis and recurrence of BC. This study examined 82 Chinese patients with BC. Of these patients, 34 underwent radical cystectomy (RC), and 48 underwent transurethral resection with intravesical instillation. In addition, multi-gene panel targeted next-generation sequencing (NGS) of the samples was performed. The mutational spectra revealed that C > T was the most common base substitution. Single nucleotide polymorphism (SNP) and deletion (DEL) were the common variant types in our cohort. The top 10 mutant genes were ROS1 (37%), PIK3CA (35%), FGFR3 (34%), BRAF (34%), ERBB2 (32%), ALK (27%), RET (27%), NTRK1 (24%), MET (23%), and EGFR (18%). FGFR3 mutations were detected more frequently in non-muscle-invasive bladder cancer (stages 0a, I) patients than in muscle-invasive bladder cancer (stage II, III, and IV) patients. The top 3 altered types of FGFR3 were p.Ser249Cys, p.Tyr375Cys, and p.Arg248Cys. This study examined the mutated types and frequency of FGFR3 and the prognosis of Chinese BC patients with FGFR mutations. We hope that our findings will enable clinical individualization strategies for BC patients to be optimized.

FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.

Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis. Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis. We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth. These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.