FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review)

Area of Science:

• Genetics and Oncology
• Molecular Biology
• Cancer Research

Background:

• The FGFR2 gene encodes crucial FGF receptors (FGFR2b/FGFR2c) with context-dependent oncogenic and anti-oncogenic functions.
• Genetic alterations like SNPs, missense mutations, and copy number gains in FGFR2 are implicated in various cancers, including breast, gastric, prostate, and bladder cancers.
• FGFR2 signaling dysregulation, driven by epigenetic and genetic factors, contributes to carcinogenesis, while loss of FGFR2b signaling can promote tumor progression and oxidative stress.

Purpose of the Study:

• To elucidate the multifaceted roles of FGFR2 in cancer development and progression.
• To explore the implications of FGFR2 genetic variations and signaling in different cancer types.
• To evaluate the therapeutic potential and risks associated with FGFR2-targeted interventions.

Main Methods:

• Analysis of FGFR2 gene structure, including single nucleotide polymorphisms (SNPs) and copy number variations.
• Investigation of FGFR2 isoform switching (FGFR2b to FGFR2c) in cancer progression.
• Assessment of FGFR2 signaling pathways, including Nrf2-mediated detoxification and epithelial-to-mesenchymal transition (EMT).
• Review of existing and emerging FGFR2-targeted therapeutic strategies (small molecules, antibodies, RNA-based therapies).

Main Results:

• FGFR2 SNPs are associated with breast cancer risk via allelic upregulation.
• FGFR2 mutations and copy number gains activate oncogenic signaling in breast and gastric cancers.
• Spliceosome dysregulation drives FGFR2 isoform switching in prostate and bladder cancers.
• Loss of FGFR2b signaling in mice increases carcinogenesis sensitivity and promotes EMT and oxidative stress.
• FGFR2 inhibitors are potential therapeutics for cancers with FGFR2 alterations.

Conclusions:

• FGFR2 signaling is a critical determinant in cancer, with both oncogenic and protective roles.
• Targeting FGFR2 offers therapeutic opportunities for specific cancer mutations and amplifications.
• Caution is advised for using FGFR2 inhibitors in cancer prevention due to potential impairment of cytoprotective mechanisms against oxidative stress.