FGFR3

Overview

FGFR3 is a receptor tyrosine kinase recurrently activated in urothelial carcinoma via hotspot missense mutations (S249C, R248C, Y373C) and FGFR3-TACC3 fusions, and is the primary actionable biomarker for the FGFR inhibitor erdafitinib.

Alterations observed in the corpus

  • Oncogenic FGFR3 alterations were present in 27.5% of urothelial tumors overall (bladder_msk_2023), with frequencies of 39% (199/504) in NMIBC, 14% (75/526) in MIBC, 43% (81/187) in localized UTUC, and 26% (59/228) in metastatic disease PMID:37682528.
  • S249C was the most frequent alteration overall; R248C was enriched in upper-tract (22%, 18/81) vs bladder (11%, 37/333; p=0.01) tumors PMID:37682528.
  • FGFR3-TACC3 fusions observed; FGFR3-fusion tumors had lower TMB than FGFR3-mutant tumors (median 5 vs 9 mut/Mb, p=0.0006) PMID:37682528.
  • Primary/metastatic FGFR3 discordance in 7/27 (26%) paired cases: 4 metastasis-only, 2 primary-only, 1 with different FGFR3 alterations in each site PMID:37682528.
  • Acquired FGFR3 kinase-domain mutations identified in serial cfDNA on erdafitinib at conserved residues (N540S, V553M, K650M, R669G); in silico modeling supports V553M as a gatekeeper allele allosterically blocking erdafitinib binding PMID:37682528.
  • Subclonal FGFR3-TACC3 fusion identified at single-cell level and by serial ctDNA in a patient with HER2+ esophagogastric cancer; the fusion expanded on-treatment and was implicated as an acquired resistance driver to pembrolizumab + trastuzumab + chemotherapy PMID:37406106.
  • FGFR3 driver fusions were detected in patients who subsequently acquired BRAF fusions as a resistance mechanism to FGFR3-targeted therapy PMID:38922339.
  • FGFR3 alterations detected in 19% of pretreatment cfDNA samples (MSK-ACCESS, 129-gene panel, median depth >15,000×) from 201 metastatic urothelial carcinoma (mUC) patients in the CALGB 90601 trial PMID:40256659.
  • Mutations and FGFR3-TACC3 fusions more common in low-grade/stage bladder cancer; 9% discordance in primary-met pairs; cfDNA detected resistance mutations (N540S, K650E, V553M) during erdafitinib therapy PMID:36543146
  • FGFR3 S249C hotspot mutations enriched in LumP urothelial carcinoma (OR 7.2, p = 6.1e-5); FGFR3-TACC3 fusions in 4% of evaluable samples in UC-GENOME cohort PMID:36333289
  • FGFR3::TACC3 in-frame fusion (GOF) in 1 GBC patient PMID:36228155
  • Listed among mutated genes in 183 LUAD cases (WES, Broad cohort) PMID:22980975
  • Amplified at 4p16.3 in the copy-number-high (serous-like) cluster 4 of endometrial cancer; this amplification newly reported in endometrial cancer PMID:23636398
  • Noted as background context in pilocytic astrocytoma genomics: FGFR3:TACC3 fusions occur in adult glioblastoma, providing conceptual parallel for kinase-domain fusion biology PMID:23817572
  • Somatic hotspot mutation in 13% of high-grade urothelial bladder carcinoma (BLCA), among the three most prevalent mutations in the cohort (TP53 34%, PIK3CA 18%, FGFR3 13%); part of the MAPK-pathway alteration set occurring in mutually exclusive distribution PMID:23897969
  • Recurrent FGFR3-TACC3 in-frame inversion fusion detected by RNA-seq in 2/164 (1.2%) GBM samples; focal co-amplification of FGFR3/TACC3 in 2.6% of GBM CNA profiles; proposed as a candidate for FGFR inhibitor trials PMID:24120142
  • Recurrent activating point mutations (confirmed TCC driver) plus FGFR3-TACC3 in-frame fusion in 2/42 (5%) bladder tumors by RNA-seq; fusion confirmed by WGS junction-spanning reads; reinforces FGFR3 as a high-value therapeutic target in BLCA PMID:24121792
  • High expression or copy-number gain supported FGFR3-inhibitor or pazopanib recommendations in NEN patients PN1, PN14, PN17, and PN25 in a precision oncology cohort PMID:24326773
  • FGFR3 kinase-activating mutations in 12% of muscle-invasive bladder cancers at canonical hotspots; recurrent in-frame FGFR3-TACC3 fusions (n=3); copy-number gain; enriched in mRNA cluster I (papillary-like); tumors with FGFR3 mutations, gains, or fusions may respond to FGFR inhibitors PMID:24476821
  • FGFR3 K650E mutation detected in the OPM2 multiple myeloma cell line used as BRAF-WT control in MAPK inhibitor assays PMID:24434212
  • Listed as a gene observed in the TCGA papillary thyroid carcinoma (PTC) cohort (thca_tcga_pub); specific alteration details not described in the narrative sections of this paper. PMID:25417114
  • G380R transmembrane-domain mutation (constitutively active, the achondroplasia allele) identified as an oncogenic activating event in cSCC PMID:25589618
  • Amplification in 2% HPV(-) vs 11% HPV(+) HNSCC; FGFR3-TACC3 fusions in 2 HPV(+) tumors PMID:25631445
  • Activating missense (e.g., S249C) in 22/23 low-grade and 27.1% of high-grade UTUC; 5 FGFR3-TACC3 gene fusions in high-grade UTUC; enriched vs UCB and associated with low grade/lower T stage; largest targetable alteration in UTUC PMID:26278805
  • FGFR3 mutation identified in one adenoid cystic carcinoma (ACYC) patient, who was enrolled on an FGFR inhibitor trial through MSK-IMPACT-guided basket study PMID:27442865
  • FGFR3 alterations (including activating mutations and fusions) were profiled across cancer types in a large-scale targeted sequencing study PMID:28336552
  • Hotspot mutations in 49% of NMIBC overall (more frequent in lower grade/stage); four fusions identified including novel FGFR3-TNIP2 and FGFR3-TACC3; mutually exclusive with ERBB2; together covers 57% of high-grade NMIBC PMID:28583311
  • FGFR3-TACC3 fusion reported for the first time in cholangiocarcinoma (CCA) in the 489-sample ICGC multi-platform cohort; this fusion was previously characterized as oncogenic in bladder cancer, glioblastoma, and lung cancer PMID:28667006
  • Hotspot S249C/Y373C mutations dominate in MIBC; enriched in luminal-papillary subtype (42/57; p<10⁻⁹) and lower-stage T2 tumors (21% vs 10% T3/T4, p=0.003); associated with better survival (p=0.04); recurrent FGFR3-TACC3 fusions (n=10); dominant driver in 44% of luminal-papillary tumors; candidate for pan-FGFR tyrosine kinase inhibitors PMID:28988769
  • Highly expressed in CR/PR vs PD melanoma patients pre-therapy (189-DEG set, q<0.20) in nivolumab-treated cohort; nominated as an immune-environment modulator predictive of anti-PD-1 response PMID:29033130
  • High FGFR3 expression is characteristic of the synovial sarcoma (SS) iCluster C4 in soft-tissue sarcoma (p=7e-20) PMID:29100075
  • FGFR3-TACC3 inframe activating kinase fusion detected in BLCA (2.0%), CESC (1.7%), and LUSC (1.2%); FGFR3 is a druggable target in 15 cancer types and shows predicted fusion-derived neoantigens among the highest in the pan-cancer atlas. PMID:29617662

Cancer types (linked)

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Primary actionable biomarker for erdafitinib; real-world ORR 40% (12/30) but median PFS 2.8 mo and OS 6.6 mo in 32 metastatic UC patients PMID:37682528.
  • Acquired second-site FGFR3 V553M/N540S kinase-domain mutations are putative resistance drivers detectable in cfDNA PMID:37682528.
  • Archival primary-tumor FGFR3 status misclassifies metastatic disease in ~26% of patients, arguing for metastatic-site or cfDNA profiling before erdafitinib selection PMID:37682528.
  • FGFR3 status did not alter PFS/OS on immune checkpoint blockade (p=0.47/0.52) PMID:37682528.

Open questions

  • Functional validation of V553M and N540S as bona fide gatekeeper mutations remains to be established PMID:37682528.
  • Whether FGFR3-isoform-specific inhibitors (TYRA300, LOXO435) will overcome erdafitinib tolerability limits and resistance is unresolved PMID:37682528.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36543146

This page was processed by crosslinker on 2026-05-14. - PMID:36333289

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22980975

This page was processed by crosslinker on 2026-05-14. - PMID:23636398

This page was processed by crosslinker on 2026-05-14. - PMID:23817572

This page was processed by crosslinker on 2026-05-14. - PMID:23897969

This page was processed by crosslinker on 2026-05-14. - PMID:24120142

This page was processed by crosslinker on 2026-05-14. - PMID:24121792

This page was processed by crosslinker on 2026-05-14. - PMID:24326773

This page was processed by crosslinker on 2026-05-14. - PMID:24476821

This page was processed by crosslinker on 2026-05-14. - PMID:24434212

This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:25589618

This page was processed by crosslinker on 2026-05-14. - PMID:25631445

This page was processed by crosslinker on 2026-05-14. - PMID:26278805

This page was processed by crosslinker on 2026-05-14. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28583311

This page was processed by wiki-cli on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29033130

This page was processed by wiki-cli on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15.