Targetable Pathways in Advanced Bladder Cancer: FGFR Signaling

Abstract

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.

Keywords: DNA; bladder cancer; erdafitinib; fibroblast growth factor receptor; kinase inhibitors; mutation; targeted therapy.

Figure 1

Overview of FGF/FGFR signaling and its dysregulation in advanced bladder cancer. (A) Basic structure of the fibroblast growth factor receptor (FGFR) family and activating mutations of FGFR3 found in advanced bladder cancer. FGFRs consist of an extracellular domain enclosing three immunoglobulin (Ig)-like domains (IgI, IgII and IgIII), a transmembrane domain, and two tyrosine kinase sub-domains. In advanced bladder cancer, activating missense mutations in FGFR3 are the dominant genetic alterations in the FGFR family proteins. These mutations are predominantly in the ligand-binding (R248C and S249C) and transmembrane (G370C, S371C and Y373C) domains, Meanwhile, activating mutations in the tyrosine kinase domain (K650E) are less common. (B) Twenty-two FGFR ligands in human. FGFs can be categorized into 3 subgroups: (1) canonical FGFs requiring heparin or heparan sulfate as a cofactor to bind FGFR; (2) endocrine FGFs or hormone-like FGFs having low affinity to heparin, and instead, high affinity of α-Klotho and β-Klotho; (3) intracellular FGFs binding to Na+ V channel. Canonical FGFs and endocrine FGFs have different specificities to different FGFRs. (C) FGF/FGFR signaling. Ligand binding to an FGFR monomer leads to receptor dimerization and trans-phosphorylation at several tyrosine residues in the intracellular domains of FGFR. This phosphorylation leads to conformational changes within the intracellular domains of FGFR and subsequent recruitment of adapter molecules to initiate signaling events within the cell. Signaling pathways for FGFRs proceed through 5 downstream cascades. Activated FGFRs phosphorylate FRS2, which in turn binds to SH2 domain containing adaptor GRB2. GRB2 then signals through either PI3K /AKT/mTOR or the RAS/RAF/MEK/MAPK cascade after binding SOS. Activated FGFRs can also phosphorylate JAK kinases, which leads to STAT activation. FGFRs can also recruit and phosphorylate PLCγ, thereby initiating signaling through the DAG/PKC or IP3-Ca2+ pathways. These FGFR signaling pathways have critical roles in cell proliferation, differentiation, mobility/invasiveness, metabolism, angiogenesis, and mitogenesis. (D) Cross-talk from other tyrosine kinase receptors after binding with their own ligands enable kinase switching and signaling compensation. These receptors include platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), angiopoietin receptors (Tie1,2) and tropomyosin receptor kinases (TRK). PDGFR and EGFR overlap with all 5 signaling cascades of FGFR. VEGFR also highly overlaps with FGFR, except for JAK/STAT activation. IGFR can activate PI3K/AKT and RAS/MEK/MAPK cascade. TIEL binding by ang1 activates PI3K/AKT signaling. TRK binding by NGF will activate RAS/MEK/MAPK, PI3K/AKT and PLCγ signaling.