FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target?

Abstract

Gastric cancer (GC) is the third leading cause of cancer-associated death worldwide. The majority of patients are diagnosed at an advanced/metastatic stage of disease due to a lack of specific symptoms and lack of screening programs, especially in Western countries. Thus, despite the improvement in GC therapeutic opportunities, the survival is disappointing, and the definition of the optimal treatment is still an unmet need. Novel diagnostic techniques were developed in clinical trials in order to characterize the genetic profile of GCs and new potential molecular pathways, such as the Fibroblast Growth Factor Receptor (FGFR) pathway, were identified in order to improve patient's survival by using target therapies. The aim of this review is to summarize the role and the impact of FGFR signaling in GC and to provide an overview regarding the potential effectiveness of anti-FGFR agents in GC treatment in the context of precision medicine.

Keywords: FGFR fusions; FGFR inhibitors; Tyrosine kinase inhibitors; bemarituzumab; fibroblast growth factor receptors; first line; next generation sequencing; precision medicine; target therapy.

Figure 1

FGFR structure and pathway. (a) FGFR structure: FGFR contains three extracellular Ig domains (domains I, II, and III), a single transmembrane helix domain and an intracellular tyrosine kinase domain. The acidic box region between Ig I and II domains can interact with substances other than FGFs. The FGF binding sites are located in domains II and III. For FGFR1-3, the alternative splicing of the second half of the Ig III domain is tissue-dependent. In the case of FGFR4, FGFR contains a single homologous FGFR-IIIc isoform. (b) FGFR pathway: Activation of the FGFR tyrosine kinase domain may activate several cellular pathways, including the RAS-RAF-MEK-ERK, the PIK3CA-AKT-mTOR, and the JAK pathways through the FGFR-associated cytosolic docking protein FRS2.