👤 J D Subiela

FGFR inhibitors are a new therapeutic option for urothelial carcinoma (UC) with FGFR2/3 alterations. In this study, we analyzed genetic alterations, co-regulation, and differential expression for 45 genes encoding FGF, FGFR, or FGF-binding proteins (FGFBPs) in five published UC cohorts (n = 3939 MIBC) and 39 UC cell lines (DepMap portal). Network analyses identified FGFR1/3 genes as critical oncogenic hubs, co-regulated with their ligands and co-receptors, and abundantly expressed at protein level in the HPA immunohistochemistry data set. Machine learning with 38 FGFR-, FGF-, and FGFBP-coding transcripts reproduced consensus molecular subtypes with high accuracy of 0.72-0.84 (Cohen's κ 0.59-0.77). FGFR3 mutations in the transmembrane/hinge region, which were enriched in luminal papillary tumors, trigger ligand-independent signaling. Conversely, overexpression of FGFR1 and its ligands and accessory protein transcripts indicates ligand-dependent FGFR1 signaling in stroma-rich and basal/squamous subtypes. The sensitivity of most DepMap UC cell lines to pan-FGFR inhibitors in the GDSC and PRISM drug screens was independent of FGFR3 alterations. In vitro, erdafitinib reduced proliferation in FGFR wild-type UC cell lines in a similar manner to FGFR3-mutated cell lines. Our findings highlight FGFR1 and FGFR3 as pivotal signaling pathways with distinct, molecular subtype-specific activation mechanisms. The results suggest that FGFR inhibitors may have therapeutic applications beyond UC tumors with FGFR2/3 alterations. Show less

FGFR3 mutations are among the most frequent genomic alterations in urothelial cancer (UC) being mainly associated with the luminal papillary (LumP) subtype. With the establishment of fibroblast growth factor receptor (FGFR) inhibitors, the treatment of UC is now shifting more and more towards personalized medicine. A systematic review using Medline and scientific meeting records was carried out according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to assess the potential role of FGFR inhibitors in combination with additional therapies for the management of UC. Ongoing trials were identified via a systematic search on ClinicalTrials.gov. A total of eleven full-text papers, ten congress abstracts, and 5 trials on ClinicalTrials.gov were identified. Following the BLC2001 and THOR study, erdafitinib is the only approved FGFR1-4 inhibitor for metastatic UC with susceptible FGFR2/3 alterations following platinum-based chemotherapy. According to the THOR data of cohort 2, erdafitinib should not be recommended in patients who are eligible for and have not received prior immune checkpoint inhibitors (ICIs). One phase 3 trial is currently evaluating the intravesical device system (TAR210) in FGFR-altered intermediate non-muscle invasive bladder cancer (MoonRISe-1). Preclinical evidence suggests that combination-based approaches could be considered to improve the efficacy of FGFR inhibitors in patients with UC. Nine phase 1b/2 trials are focusing on the combination of FGFR inhibitors with ICIs, chemotherapy, or enfortumab vedotin. In metastatic disease, some preliminary analyses have reported promising results from these combinations (e.g. NORSE and FORT-2 trial). However, no phase 3 trial is terminated, so there is currently no level 1 evidence with long-term outcomes to support the combination of FGFR inhibitors with ICIs, chemotherapy, or targeted therapies. A better understanding of the different mechanisms of action to inhibit FGFR signaling pathways, optimal patient selection and treatment approaches is still needed. Show less