Abstract
Simple SummaryAround 20% of advanced bladder cancer patients carry unfavorable genetic alterations in the fibroblast growth factor receptor 3 (FGFR3) gene. This review summarizes recent findings from published research and clinical trial data focusing on developing and testing therapeutics that inhibit the increased activities of these genetic alterations. Possible mechanisms of drug resistance observed in some patients are also discussed. This review also discusses clinical findings from studies combining FGFR inhibition with other targeted inhibitors and/or immunotherapy to examine whether outcomes may be improved, especially in patients who have less than optimal responses to FGFR3-directed monotherapy.Bladder cancer is the 10th most commonly diagnosed cancer in the world, accounting for around 573,000 new cases and 213,000 deaths in 2020. The current standard treatment for locally advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. The significant progress being made in the genomic and molecular understandings of bladder cancer has uncovered the genetic alterations and signaling pathways that drive bladder cancer progression. These developments have led to a dramatic increase in the evaluation of molecular agents targeting at these alterations. One example is Erdafitinib, a first-in-class FGFR inhibitor being approved as second-line treatment for locally advanced or metastatic urothelial carcinoma with FGFR mutations. Immunotherapy has also been approved as second-line treatment for advanced and metastatic bladder cancer. Preclinical studies suggest targeted therapy combined with immunotherapy has the potential to markedly improve patient outcome. Given the prevalence of FGFR alternations in bladder cancer, here we review recent preclinical and clinical studies on FGFR inhibitors and analyze possible drug resistance mechanisms to these agents. We also discuss FGFR inhibitors in combination with other therapies and its potential to improve outcome.
Highlights
Once a tumor has invaded into the muscle layer of the bladder, bladder cancer is diagnosed as muscle invasive or advanced bladder cancer
A number of studies have shown that bladder cancer cells harboring FGFR3 hyperactivating mutations and FGFR3-TACC3 fusion are responsive to FGFR3 inhibition [52,53,54,55]
Infigratinib (BJG398) is an FGFR1–3-selective oral tyrosine kinase inhibitor [58] shown in a phase II study to reduce the size of tumors bearing FGFR3 alterations and stabilize disease in metastatic urothelial carcinoma patients [59]
Summary
IGFRand signaling tyrosine kinase receptors with own ligands enable kinase switching can activate PI3K/AKT and RAS/MEK/MAPK cascade. Canonical FGFs include five paracrine subfamilies: FGF1, FGF4, FGF7, FGF8, and FGF9 subfamilies, and bind to four tyrosine kinase FGF receptors (FGF1-4) via a high-affinity interaction with co-factor heparin or heparan sulphate, followed by FGFR activation, dimerization, and activation of cytoplasmic signaling transduction pathways [15,28,29]. Endocrine or hormone-like FGFs (FGF19 subfamily) have low affinity to FGFRs in the presence of heparin/heparan sulphate [30,31], and instead require co-receptors α-and β-Klotho to bind, thereby activating FGFRs to regulate cell growth and metabolism [32,33,34,35,36]. The intracellular FGFs (FGF11 subfamily) are non-secretory FGFs that interact with and regulate voltage-gated sodium channels and other molecules, such as p65 and NF-κB, to regulate neuronal development and function [37,38,39,40,41]
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