Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

Abstract

Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions.

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients

“…Growing evidence suggests that FGFR GAs are associated with worse outcomes in different tumor types [ 14 , 15 , 16 ]. In spite of the general correlation of FGFR GA with lower grades and stages of nonmuscle-invasive UC, there is no evidence to support that FGFR GAs are associated with a favorable phenotype once urothelial carcinoma advances [ 17 ].…”

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

“…Ectopic overexpression of FGF1 has been shown to be highly associated with cancer progression and prognosis in bladder cancer [39] . Recent studies have demonstrated that FGF inhibitors can be used to treat locally advanced/metastatic UC by targeting tumor-specific oncogenic signaling involving the tumor immune microenvironment [40] . Additionally, LRRC59 is necessary for the nuclear import of oncoprotein protein phosphatase 2A (PP2A, CIP2A) [41] .…”

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

“…Tumor vasculogenesis is a complex process driven by the VEGF, PDGF, EGF, FGF, and ANG families, with VEGF-VEGFR and FGF2-FGFR1/2 signaling playing key roles by promoting endothelial cell proliferation and migration, duct formation, and protease production [ 18 , 144 – 146 ]. Assays on murine brain capillary endothelial cells (MBEC) point to enhanced chemotaxis of MBEC by FGF2/FGFR, an effect is associated with MAPK signaling [ 17 , 147 ].…”

“…FGFR-TKI induces normalization of the tumor vascular system, which is a prerequisite for the extravasation of immune cells and T-lymphocyte infiltration [ 144 , 145 , 162 ]. Anti-angiogenic therapy including anti-FGF signaling has been well-documented in numerous studies to enhance the efficacy of immunotherapy [ 163 – 166 ].…”