Fibroblast Growth Factor Receptor Gene Research Articles

Abstract LB-92: Using immunohistochemistry to evaluate FGFR3 gene fusion recurrence and clinical associations in astrocytomas

Abstract Aberrant activation of fibroblast growth factor receptor 3 (FGFR3) has been reported to be tumorigenic in various cancer types. When FGFR3 is fused with another gene, most commonly with transforming acidic coiled coil 3 (TACC3), it can escape miRNA-mediated regulation and remain constitutively active most likely due to the dimerization via the domains of TACC3 or another fusion partner. Among brain cancers, gene fusions involving FGFR3 have been detected in glioblastoma and certain low grade gliomas. Furthermore, FGFR3-TACC3 fusion positive glioma cells have responded well to targeted therapies. The endogenous FGFR3 protein levels are extremely low in brain partly due to miR-99a-mediated regulation and gene fusions lead to prominent protein expression. In previous studies, FGFR3 fusion recurrence and fusion partners have been analyzed only in limited patient cohorts and there are no reports about their clinical associations. In this study, we have performed immunohistochemistry for FGFR3 on tissue microarrays with over 750 clinical astrocytoma samples (including grade 1-3 astrocytomas and glioblastomas). FGFR3 positive staining has been detected in subpopulations of all included tumor grades. The observed recurrences (1.8%-6.2%, depending on the grade) are consistent with previous sequencing-based studies. To validate immunohistochemistry-based approach for FGFR3 fusion detection, we are using frozen tumor material to confirm the presence of fusion with Western blotting and with PCR followed by Sanger sequencing. Furthermore, we have associated FGFR3 staining scores with clinical records for all the cases. FGFR3 staining is more common in females than males both in astrocytoma (7.6% vs 2.2%, pearson chi-square p-value 0.004, n=752) and glioblastoma cohorts (8.9% vs 2.1%, pearson chi-square p-value 0.008, n=494). In addition, FGFR3-staining negatively associates with aberrant p53 staining indicating p53 mutation (FGFR3-positive cases: 5.8% vs 1.8% in p53 low vs high groups, respectively, pearson chi-square p-value 0.030, n=399). Altogether, this study evaluates the suitability of immunohistochemical methods for FGFR3 fusion detection as well as investigates their recurrence and clinical significance in astrocytomas. Citation Format: Kirsi J. Granberg, Birgitta Lehtinen, Matti J. Annala, Hannu Haapasalo, Matti Nykter, Wei Zhang. Using immunohistochemistry to evaluate FGFR3 gene fusion recurrence and clinical associations in astrocytomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2014-LB-92

Abstract 4728: FGFR1 gene amplification in small cell lung cancer

Abstract Background: Fibroblast growth factor receptor 1 (FGFR1) received special attention from many clinicians according to finding that FGFR1 played a critical role in many human cancers. Some clinical trials using FGFR1 targeting agents are in progress especially in breast cancer and squamous non-small cell lung cancer. Recently, FGFR1 amplifications were also found in about 5.6-6% of small cell lung cancer (SCLC) by gene copy number analysis and FISH. Methods: Tumor tissues from 113 patients diagnosed with SCLC from October 2009 to February 2013 in YUHS, Korea were collected. FGFR1 FISH assay was performed on the tissue microarray using FISH probe that hybridized to the band 8p12-8p11.23 (FISH probes were provided by Abbott Molecular, Abbott Park, IL). Results: Thirty-two patients with limited-stage disease (LD) and eighty-one patients with extensive-stage disease (ED) were enrolled. Fourteen patients were female. Among 113 tumor samples, 5 samples (4.4%) showed FGFR1 amplification. All 5 samples were obtained from the patients with ED. The patients with FGFR1 amplification more frequently had pleural metastasis at the time of diagnosis (80% vs. 26%, P=0.022). In ED, the patients with FGFR1 amplification represented shorter disease free survival from first line chemotherapy (Hazard ratio [HR], 4.469; 95% confidence interval [CI], 1.600-12.483; P=0.004) and second line chemotherapy (HR, 6.533; 95% CI, 1.700-25.108; P=0.006) than the patients without FGFR1 amplification in multivariate analysis. Median overall survival time was 8.2 months in the patients with FGFR1 amplification and 10.2 months in the patients without FGFR1 amplifications (P=0.296). Conclusion: FGFR1 amplification is a poor potential predictive biomarker of standard chemotherapy, necessitating further research in a large cohort of SCLC. The validity of targeting FGFR1 in SCLC should be confirmed in a clinical trial. Citation Format: Ji Soo Park, Jae-Seok Lee, Hyo Sup Shim, Hye Ryun Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. FGFR1 gene amplification in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2014-4728

Abstract CT325: First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors

Abstract Background: JNJ-42756493 is an FGFR 1, 2, 3, and 4 inhibitor with nanomolar affinity, orally bioavailable, and has demonstrated a broad spectrum antitumor activity in cell line, xenograft and patient-derived explant models with abnormality in FGFR signaling pathway such as FGFR gene amplification, mutation and translocation. Methods: A multipart phase 1 first in human study of JNJ-42756493 was initiated in advanced solid tumor patients (NCT01962532) including, Part 1 dose-escalation to determine the recommended phase 2 dose (RP2D) based on safety, pharmacokinetic, and pharmacodynamic data; Part 2 biopsy cohort to confirm the RP2D and Part 3 expansion phase to evaluate anti-tumor activity in NSCLC, SCLC, Breast cancer and other solid tumor patients with FGFR gene amplification, mutation or translocation at RP2D. Multiple biomarkers from tissue (including phospho-FGFR, phospho-Erk and phospho-S6) and serum (phosphate, calcium, Vitamin D, PTH and FGF23) were also assessed in the study. Results: At data cut-off (22 October 2013), total of 28 patients had been treated at 5 dose levels (0.5, 2, 4, 6 and 9 mg daily continuously) in Part 1 of the study. JNJ-42756493 appeared safe, did not generate any dose-limiting toxicities or any drug related severe adverse events. One patient from 4 mg cohort died after receiving 6 doses in Cycle 1, autopsy indicated a serious adverse event (SAE) of pulmonary edema which not related to the study drug. The most common adverse events (AEs) were hyperphosphatemia (57%), asthenia (46%), dry mouth (32%), abdominal pain (29%), diarrhea (25%), vomiting (25%), decreased appetite (21%) and constipation (21%). Grade 1 or 2 hyperphosphatemia was managed by co-administration of phosphate lowering therapy and by treatment interruption, other AEs were generally mild to moderate. No clinically significant cardiac safety findings were observed. Pharmacokinetics was linear and predictable with a half-life of ∼50 hours. Dose levels ≥ 6mg achieved plasma concentrations predicted to be efficacious from preclinical experiments. Dose dependent changes in biomarkers including increases in phosphate, FGF23 and calcium and decreases in PTH were observed in blood, evaluation of biomarker response in tissue is ongoing. A bladder cancer patient with lung metastasis harboring a FGFR3-TACC3 translocation treated at 9 mg had a confirmed PR. 9 mg was declared as the first RP2D, but safety evaluation of JNJ-42756493 at higher doses is ongoing. Conclusions: JNJ-42756493 has excellent pharmaceutical properties and appeared safe with manageable side effects at dose levels that elicit anti-tumor activity. Citation Format: Rodrigo Dienstmann, Rastilav Bahleda, Barbara Adamo, Jordi Rodon, Andrea Varga, Anas Gazzah, Suso Platero, Hans Smit, Timothy Perera, Bob Zhong, Kim Stuyckens, Yusri Elsayed, Chris Takimoto, Vijay Peddareddigari, Josep Tabernero, Feng Roger Luo, Jean-Charles Soria. First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT325. doi:10.1158/1538-7445.AM2014-CT325

Association of physical activity and polymorphisms in FGFR2 and DNA methylation related genes with breast cancer risk

PurposePhysical activity, a protective factor for breast cancer, increases the level of DNA methylation. Fibroblast growth factor receptor 2 (FGFR2), a confirmed breast cancer susceptibility gene, is predisposed to be methylated. Therefore, DNA methylation related genes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and DNA methyltransferase (DNMT), together with physical activity and FGFR2, may interact with each other to effect breast cancer risk. MethodsA total of 839 incident breast cancer cases and 863 age-matched controls from Guangzhou, China were included in this study. We used questionnaires to assess physical activity in metabolic equivalent (MET)-h/week/year and a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform to ascertain genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models. ResultsExercise activity and FGFR2 rs2981582 were confirmed to be associated with breast cancer risk, and were found to significantly interact (P for multiplicative and additive interactions=0.045 and 0.021, respectively). Women who had CT/TT genotypes of FGFR2 rs2981582 and experienced exercise activity <3 MET-h/week/year had significantly increased risk (OR=3.15, 95% CI=2.28–4.35) compared to women with CC genotype and ≥3 MET-h/week/year. There was also a significant interaction between FGFR2 rs2981582 and MTHFR rs1801133 on breast cancer risk (P for multiplicative and additive interactions=0.039 and 0.023, respectively). ConclusionWe found both a gene–environment (FGFR2-exercise activity) and a gene–gene (FGFR2–MTHFR) interaction on breast cancer risk. Our results suggest that environmental factors, such as physical activity, may be able to counteract genetic susceptibility to breast cancer.

Prognostic value of FGFR gene amplification in patients with different types of cancer: a systematic review and meta-analysis.

BackgroundFibroblast growth factor receptor (FGFR) gene amplification has been reported in different types of cancer. We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with cancer.MethodsA search of several databases, including MEDLINE (PubMed), EMBASE, Web of Science, and China National Knowledge Infrastructure, was conducted to identify studies examining the association between FGFR gene amplification and cancer. A total of 24 studies met the inclusion criteria, and overall incidence rates, hazard risk (HR), overall survival, disease-free survival, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies.ResultsIn the meta-analysis of 24 studies, the prevalence of FGFR gene amplification was FGFR1: 0.11 (95% CI: 0.08–0.13) and FGFR2: 0.04 (95% CI: 0.02–0.06). Overall survival was significantly worse among patients with FGFR gene amplification: FGFR1 [HR 1.57 (95% CI: 1.23–1.99); p = 0.0002] and FGFR2 [HR 2.27 (95% CI: 1.73–3.00); p<0.00001].ConclusionsCurrent evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non-FGFR gene amplified cancers.

RBFOX and SUP-12 sandwich a G base to cooperatively regulate tissue-specific splicing.

Tissue-specific alternative pre-mRNA splicing is often cooperatively regulated by multiple splicing factors, but the structural basis of cooperative RNA recognition is poorly understood. In Caenorhabditis elegans, ligand binding specificity of fibroblast growth factor receptors (FGFRs) is determined by mutually exclusive alternative splicing of the sole FGFR gene, egl-15. Here we determined the solution structure of a ternary complex of the RNA-recognition motif (RRM) domains from the RBFOX protein ASD-1, SUP-12 and their target RNA from egl-15. The two RRM domains cooperatively interact with the RNA by sandwiching a G base to form the stable complex. Multichromatic fluorescence splicing reporters confirmed the requirement of the G and the juxtaposition of the respective cis elements for effective splicing regulation in vivo. Moreover, we identified a new target for the heterologous complex through an element search, confirming the functional significance of the intermolecular coordination.

A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-014-1803-2) contains supplementary material, which is available to authorized users.

Fibroblast growth factor receptors: multifactorial-contributors to tumor initiation and progression.

Fibroblast growth factor receptors (FGFRs), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) are tightly associated with many biological processes such as organ development, cell proliferation and migration. Studies over the past decades have validated the pivotal roles FGFRs play in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. Interestingly, FGFR mutations in somatic cells leading to tumorigenesis and those in germ cells leading to developmental disorders are identical, suggesting that FGFR mutations result in different diseases due to their spatio-temporal expression. Thus, discoveries in developmental biology may also be applicable to cancer. FGFRs regulate the expression and/or the activity of a myriad of molecules (e.g. matrix metalloproteinases (MMPs) and Snail) that are tightly linked to tumorigenesis by four main signaling pathways (RAS-MAPK, PI3K-AKT, PLCγ-PIP2, and STAT), as well as other minor branches. Epigenetic and genetic alteration of FGFR genes, including DNA methylation, histone remodeling, microRNA regulation, single nucleotide polymorphisms (SNPs), gene missense mutations, amplification, and fusion of FGFRs with other genes, which result in gain or loss of FGFR function, have been identified in many types of cancer. In this review, we focus in particular on recent advances in the relationship between FGFR disorders and tumorigenesis.

What can FGF23 do without Klotho?

What can FGF23 do without Klotho?

Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event

The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course.

Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells

Somatic alterations of Fibroblast Growth Factor Receptors (FGFRs) have been described in a wide range of malignancies. A number of anti-FGFR therapies are currently under investigation in clinical trials for subjects with FGFR gene amplifications, mutations and translocations. Here, we develop cell line models of acquired resistance to FGFR inhibition by exposure of cell lines harboring FGFR3 gene amplification and translocation to the selective FGFR inhibitor BGJ398 and multi-targeted FGFR inhibitor ponatinib. We show that the acquisition of resistance is rapid, reversible and characterized by an epithelial to mesenchymal transition (EMT) and a switch from dependency on FGFR3 to ERBB family members. Acquired resistance was associated with demonstrable changes in gene expression including increased production of ERBB2/3 ligands which were sufficient to drive resistance in the setting of FGFR3 dependency but not dependency on other FGFR family members. These data support the concept that activation of ERBB family members is sufficient to bypass dependency on FGFR3 and suggest that concurrent inhibition of these two pathways may be desirable when targeting FGFR3 dependent cancers.

Hearing Loss in Syndromic Craniosynostoses: Introduction and Consideration of Mechanisms

There are a number of craniosynostosis syndromes with hearing loss-including Muenke, Apert, Pfeiffer, Crouzon, Beare-Stevenson, Crouzon with acanthosis nigricans, and Jackson-Weiss syndromes-that result from mutations in the fibroblast growth factor receptor (FGFR) genes. Studies of FGFRs and their ligands, fibroblast growth factors (FGFs), have revealed clues to the precise contribution of aberrant FGFR signaling to inner ear morphogenesis and the hearing loss encountered in craniosynostoses. The purpose of this article is to review basic studies of FGFRs with emphasis on their function and expression in the inner ear and surrounding structures. A Medline search was performed to find basic science articles regarding FGFR, their ligands, and their expression and relevant mouse models. Additional items searched included clinical descriptions and studies of individuals with FGFR-related craniosynostosis syndromes. The FGF signaling pathway is essential for the morphogensis and proper function of the inner ear and auditory sensory epithelium. The variable auditory phenotypes seen in individuals with Muenke syndrome may have a genetic basis, likely due to multiple interacting factors in the genetic environment or modifying factors. Further analysis and studies of mouse models of Muenke syndrome, in particular, may provide clues to the specific effects of the defining mutation in FGFR3 in the inner ear not only at birth but also into adulthood. In particular, investigations into these models may give insight into the variable expression and incomplete penetrance of this phenotype.

FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer.

The fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copy-number variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCR-SNaPshot and FGFR3 protein expression by standard immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p < 0.01) between mutant and wild-type tumours with the FGFR3 mutation pointing to more favourable BC. However, if the BC exhibited wild-type FGFR3, FGFR3 protein status had no influence on grade and (sub)stage. We found six tumours with more than or equal to three copies of FGFR3. Only 1 of 22 wild-type tumours with over-expression of FGFR3 had more than or equal to three gene copies. In initially diagnosed T1 BC, only the FGFR3 mutation was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 over-expression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with over-expression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy.

Molecular identification of a TPR-FGFR1 fusion transcript in an adult with myeloproliferative neoplasm, T-lymphoblastic lymphoma, and a t(1;8)(q25;p11.2)

The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal abnormalities involving rearrangement of the fibroblast growth factor receptor 1 (FGFR1) gene. We report herein a rare case of a t(1;8)(q25;p11.2) with a TPR-FGFR1 rearrangement, in which the patient presented with myeloproliferative neoplasm-like symptoms and T-lymphoblastic lymphoma. Sequence analysis revealed a fusion transcript with exon 22 of the TPR gene joined to exon 13 of the FGFR1 gene, which is a novel breakpoint for the TPR gene in the TPR-FGFR1 rearrangement.

Prognostic value of FGFR1 gene copy number in patients with non-small cell lung cancer: a meta-analysis.

A number of studies have investigated the relationship between fibroblast growth factor receptor1 (FGFR1) gene copy number and survival in non-small cell lung cancer (NSCLC) patients. However, conclusions reported by different parties seem to be inconsistent, especially regarding the differences among different histopathologic subtypes. To derive a more precise estimate of the prognostic significance of FGFR1 gene copy number, we have reviewed published studies and carried out a meta-analysis. The meta-analysis was conducted in accordance with PRISMA guidelines. The required data for estimation of individual hazard ratios (HRs) for survival were extracted from the publications and an overall HR was calculated. We identified 6 eligible studies, all dealing with NSCLC. The global quality score ranged 32.5-80%, with a median of 53.33%. For FGFR1 amplification in three studies including differed according to histological type, the overall RR was 0.86 which 95% confidence interval (CI) was 0.75 to 0.99 and P value was 0.048. Combined HR for the six evaluable studies was 1.17 (95% CI: 0.95 to 1.43). In the subgroup of squamous cell lung cancer (SQCC), the combined HR was 1.24 (95% CI: 0.89 to 1.73). For the Asian populations' studies, the combined HR was 1.67 (95% CI: 1.1 to 2.52). FGFR1 amplification significantly was more frequent in SQCC. FGFR1 was not associated with poorer survival in patients with NSCLC. Furthermore studies will be needed in terms of survival implications.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I–II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398.

8034 Background: Identifying molecular drivers in lung squamous cell carcinoma (SCC) is a major medical need since no targeted therapy is available yet for this subtype. Fibroblast growth factor receptors (FGFRs) are physiologically involved in cell proliferation and survival. Genetic alteration of FGFR genes leads to deregulated activation in various cancers, and FGFR1 amplification has been detected in lung SCC. Here, we report on patients (pts) with FGFR1-amplified lung SCC treated in a phase 1 study of BGJ398, a potent, selective pan-FGFR inhibitor. Methods: While this phase 1 dose-escalation study enrolled pts ≥ 18 years of age with any FGFR genetically altered tumor, we report here on the subgroup of pts with FGFR1-amplified advanced or metastatic lung SCC treated with 100 or 125 mg BGJ398 once daily in 28-day cycles. Pts who had progressed following at least 1 line of therapy, including platinum, were eligible for enrollment. FGFR1-amplified tumors were identified by fluorescent/chromogenic in situ...

Exploratory biomarker analysis of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors.

11010 Background: AZD4547 is a selective inhibitor of FGFR 1, 2, and 3, with activity in patient-derived explant models with FGFR gene amplification. Study 1C1 assessed safety and clinical activity...

Characterization of Fibroblast Growth Factor Receptor 1 in Small-Cell Lung Cancer

There remains a significant therapeutic need for small-cell lung cancer (SCLC). We and others have reported high frequency of copy number gains in cytogenetic bands encoding fibroblast growth factor receptor 1 (FGFR1) in SCLC tumors and cell lines. Thirteen SCLC cell lines and 68 SCLC patient tumor samples were studied for FGFR1 amplification. Growth inhibition assays were performed using PD173074, a pan-FGFR inhibitor to determine the correlation between FGFR1 expression and drug sensitivity. We did not detect FGFR1 mutations in SCLC cell lines. Focal amplification of FGFR1 gene was found in five tumor samples (7%), with high-level focal amplification in only one tumor sample (1%). Amplification owing to polysomy of chromosome 8, where FGFR1 locates, was observed in 22 tumor samples (32%). There was no correlation between FGFR1 gene copy number and messenger RNA expression or protein expression in SCLC cells. FGFR inhibitor sensitivity correlated with FGFR1 copy number determined by real-time polymerase chain reaction assay (r= -0.79; p = 0.01). FGFR1 gene mutations and focal amplification are rare in SCLC, but polysomy of chromosome 8 is relatively common. FGFR1 copy number gain predicts sensitivity to FGFR inhibition, and FGFR expression correlates inversely with chemosensitivity.

Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene

Kallmann Syndrome (KS) is a genetic disease of embryonic development which is characterized by the association of hypogonadotropic hypogonadism (HH) due to a deficit of the gonadotropin-releasing hormone (GnRH) and a hypo/anosmia (including a hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs). Even though it is a genotypically and phenotypically heterogeneous clinical disease, there are some key genes related to KS (KAL1, FGFR1 (KAL2), GNRHR, KISSR1 (GPR54), GNRH1, NELF and PROK2). The aim of this study was to present a case report of a genetic diagnosis of KS linked to the presence of mutations in the FGFR1 (fibroblast growth factor receptor 1, also known as KAL2) gene. This diagnosis was made in a 44-year old female affected by a hypogonadism for which she had received intermittent treatment until she was 30 years old based on the patient's own decision. The molecular analysis of FGFR1 identified the mutation c. 246_247delAG (p.T82Xfs110) in heterozygosis on exon 3 of the KAL2 gene. This is the first report of this mutation related to idiopathic hypogonadotrophic hypogonadism (IHH).