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Petrillo, A. FGFR Pathway Inhibition in Gastric Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/18218 (accessed on 25 December 2024).
Petrillo A. FGFR Pathway Inhibition in Gastric Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/18218. Accessed December 25, 2024.
Petrillo, Angelica. "FGFR Pathway Inhibition in Gastric Cancer" Encyclopedia, https://encyclopedia.pub/entry/18218 (accessed December 25, 2024).
Petrillo, A. (2022, January 13). FGFR Pathway Inhibition in Gastric Cancer. In Encyclopedia. https://encyclopedia.pub/entry/18218
Petrillo, Angelica. "FGFR Pathway Inhibition in Gastric Cancer." Encyclopedia. Web. 13 January, 2022.
FGFR Pathway Inhibition in Gastric Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/life12010081

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.

gastric cancer FGFR fusions

1. Introduction

Gastric cancer (GC) is the third leading cause of cancer-associated death worldwide following lung and colorectal cancer [1]. Interestingly, its incidence varies geographically across the globe. While in Western countries, the incidence of GC decreased over the past decades, the numbers of newly diagnosed GC cases increased, especially in Asia and Africa [2][3][4]. Next to Helicobacter Pylori infection, lifestyle factors, such as alcohol intake and smoking, as well as genetic risk factors have been associated with GC development [5][6][7][8].
Unfortunately, the majority of patients are diagnosed within an advanced stage of disease [9]. In metastatic GC (mGC), systemic chemotherapy remains the standard of care [10], with median overall survival (OS) around 12 months when treated with combinational cytotoxic agents [10]. Thus, to improve patients’ survival, understanding the molecular mechanisms leading to GC development is of great importance.
Histopathological and molecular intra- and intertumoral heterogeneity are major hallmarks of GC and histological classifications, such as Laurén, are not sufficient to stratify patients towards a personalized treatment management [11]. Using novel diagnostic techniques, such as next generation sequencing, the characterization of genetic profile of GCs yielded potential novel therapeutic targets [12][13][14].
One of the first targeted treatments approved in GC was the monoclonal antibody trastuzumab that targets the Human Epidermal Receptor 2 (HER2). HER2 is overexpressed or amplified in 12–20% of all GC cases [15]. Trastuzumab in combination with chemotherapy showed an improved OS and progression-free survival (PFS) in patients harboring a HER2-positive mGC within the phase III ToGA trial [16]. Furthermore, GCs showing a microsatellite instable-high (MSI-H) or a damaged mismatch repair genes (dMMR) status are sensitive to immune checkpoint inhibitor treatment [17]. The anti-Programmed Cell Death 1 (PD-1) antibody pembrolizumab yielded an impressive response and extension of survival in MSI-H/dMMR mGC patients [18].
In this perspective of precision oncology, various new potential molecular pathways could represent novel targets for drug development in GC, such as the Fibroblast Growth Factor Receptor (FGFR) one [19]. Therefore, this review aims to summarize the role and impact of FGFR signaling and to highlight the effectiveness of anti-FGFR therapeutics in GC.

2. The FGFR Signaling Pathway and Its Alterations in Gastric Cancer

The FGFR has four notable family members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR-4 [20]. The substrate-binding selectivity and tissue distribution of these receptors are different for each receptor [21]. Another source of heterogeneity and ligand-specificity originates from alternative splicing; the four FGFR genes may splice into 48 distinct isoforms [22]. The receptor has three main components: the three extracellular Ig-like domains, a transmembrane helix, and an intracellular tyrosine kinase domain. Alternative splicing of the IgIII loop regulates the FGFR’s ligand specificity, resulting in b- and c-variants of the receptors with different biological effects. These splice variants’ tissue-specific expression controls interactions in embryonic development, tissue maintenance and repair, and cancer. The IIIb variant is principally expressed by epithelial cells, while IIIc is expressed by mesenchymal cells. The formation of the IIIb and IIIc splice variants are mutually exclusive (Figure 1a) [23].
Life 12 00081 g001 550
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.
Beyond the heterogeneity of the receptors, several fibroblast growth factors (FGFs) as ligands may activate each receptor, and some FGFs can also activate several other receptors. In particular, FGFs are the most extensive family of growth factor ligands. The structurally related FGF ligands are further subdivided according to their sequence homology [21][24]: FGFs 1–10 and 16–23 are ligands for the FGFR, whereas FGFs 11–14 are cytosolic FGF molecules that operate independently of the receptor [25].
FGFRs may form both homodimers and heterodimers that are stabilized by a heparin sulfate proteoglycan (HSPG) during activation [26]. When FGFRs are activated, their phosphorylated intracellular tyrosine kinase domain may activate several cellular pathways, including the RAS-RAF-MEK-ERK, the PIK3CA-AKT-mTOR and the JAK pathways. The activation of these downstream pathways requires using the FGFR-associated cytosolic docking protein FRS2 and its interaction with other proteins (GRB2, SOS, GAB1, and phospholipase C gamma) [27][28][29][30][31]. Activating these entire signaling pathways may influence angiogenesis, mitogenesis, differentiation, proliferation, changes in tissue homeostasis, and invasion processes (Figure 1b).
Gene fusions, translocations, mutations and amplifications of the FGFR gene have all been reported in cancer. Notably, amplification of the FGF genes was also reported. According to the comprehensive review by Helsten et al., FGFR1 mutations, FGFR2 amplifications and FGFR3 rearrangements are the most common FGFR alterations in GC. These alterations may sometimes be discovered as co-occurring concurrently [32].
A recent article from China summarized the alterations of the FGFR1-4 genes in 5557 solid tumors, including 254 cases of GC. In this analysis, FGFR1-4 aberrations occurred in 12.2% of the GC samples. Amplifications were most prevalent, followed by rearrangements and mutations. Most frequent alterations were detected in the FGFR2 gene, followed by the FGFR1, and to a lesser extent in FGFR3 and FGFR4 genes [33].
Another retrospective analysis identified FGFR alterations in 7% (745/10,582) of GC cases [34]. FGFR2 amplifications are more common in microsatellite-stable (MSS) and TP53 mutant, or MSS/epithelial-mesenchymal transition (EMT) subtypes, according to the Asian Cancer Research Group (ACRG) classification [35]. As per TCGA classification, FGFR2 amplifications are more common in the chromosomal instability (CIN) and genomically stable (GS) subtypes [12][36].
In a study of Chinese patients with GC, FGFR2 amplification was found in 4.1 percent (11/267) of GC cases, especially in the diffuse histology subtype [37]. Another study identified 20% (5/25) of GC to carry the potentially targetable FGFR3-TACC3 (F3T3) fusion [38][39].
Acquired fusions may lead to acquired resistance to FGF-directed therapy. In the case of FGFR2 inhibition of amplified GC, the development of specific fusion proteins may lead to acquired resistance to FGFR2 inhibition. An example of this is the FGFR2-ACSL5 fusion protein, which has been demonstrated to lead to resistance by Kim et al. [40].
According to a preclinical study, another mechanism of acquired resistance to FGFR2 inhibition may be the emergence of a JHDN1D-BRAF fusion, leading to the stimulation of the RAF-MEK pathway. This finding could give a therapeutic basis for employing MEK or RAF inhibitors to prevent resistance from developing or to treat patients who have developed acquired resistance due to the JHDN1D-BRAF fusion [41].

3. A Pharmacological Overview on the Anti-FGFR Agents

FGF is a growth protein secreted from fibroblasts and stored near the basal membrane of endothelial cells. As already mentioned, the activation of the FGFR pathway can affect endothelial cell proliferation and differentiation [39], which both are important for embryonic development, wound healing and intra-tumoral angiogenesis [42]. Modulation of endothelial biology and angiogenesis in cancer is common practice since the appearance of vascular endothelial growth factor blockers (VEGFs). Anti-VEGFs are the main anti-angiogenic agents used in the management of gastrointestinal malignancies, even if the results in GC patients were under the expectations [19]. In this regard, the interest in tumor microenvironment as an active player in the process of tumorigenesis and metastatization has led to identify some new molecules that could be targeted with novel drugs. In particular, available data demonstrated that FGF-2/FGFR-2 interaction might bypass the role of the VEGF/VEGFR pathway, acting as a playmaker in the process of angiogenesis and proliferation, especially in GC [19].
Based on this background, several FGFR inhibitors are being developed. TKIs are the most common FGFR antagonists, especially for pretreated cancers with intrinsic resistance to chemotherapy and target therapy [43]. First-generation TKIs are multi-target inhibitors that include the four main isoforms of FGFR and other signaling proteins of the tumor microenvironment, such as VEGFR, KIT, and RET. The multikinase inhibition was associated with severe adverse effects in the landmark trials that limited their clinical use [20]. Since then, refinement of molecular techniques for the design of target-specific molecules and careful selection of patients have demonstrated the potential benefit of FGFR blockade in the growing portfolio of cancer drugs, especially in tumors with poor survival, such as cholangiocarcinoma [44]. A recent study showed that among patients with tumors driven by FGFR aberrations, 76% would be considered ineligible for target therapy due to currently approved indications, comprising 15 different tumor types, potentially susceptible to therapy with TKIs [45].
Among the newer molecules, erdafitinib and pemigatinib are the two TKIs with accelerated regulatory approval, decreasing cell viability by inhibiting FGFR phosphorylation and block signaling. Both medications are contingent upon FGFR alterations; therefore, they are not active in the absence of these alterations [46]. Erdafitinib is an orally active small potent TKI of FGFR1–4. In vivo data shows that it is a potent and selective pan-FGFR inhibitor, including downstream signaling, resulting in a potent anti-proliferative activity, and its intracellular lysosomal localization results in sustained pathway inhibition, with Growth Inhibition 50% (GI50 or IC50) values of 1.2, 2.5, 3.0, and 5.7 nM/L for FGFR1-4 respectively [47]. The results observed in advanced urothelial carcinoma with FGFR2 and FGFR3 genetic alterations granted it accelerated approval by regulating agencies [48].
Pemigatinib is another orally active agent that targets FGFR1, 2 and 3 with IC50 values of less than 2 nM. Pemigatinib also inhibits FGFR4 in vitro at a much higher concentration than those that inhibit FGFR1, 2, and 3. [49]. After the results of the Fight-202 trial, pemigatinib received accelerated approval by the American food and drug administration (FDA) and conditional marketing authorization by the European medicines agency (EMA) for cholangiocarcinoma harboring FGFR2 rearrangements or fusions [50].
Monoclonal antibodies have also represented a breakthrough in advanced esophagogastric and GC protocol designs. Bemarituzumab, an IgG1 antibody targeting FGFR2b ligand-binding domain, blocks ligand-dependent activation of FGFR2b by interfering with the union to FGF; it also mediates antibody-dependent cytotoxicity [51].

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