2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fibroblast growth factors (FGFs) and their receptors (FGFRs) are implicated in numerous cancers, yet targeted therapies have limited clinical success.
• RNA splicing of FGFRs significantly impacts their function and interactions, complicating drug development strategies.
• FGFR2, in particular, exhibits splice-dependent functions critical to cancer cell behavior.

Purpose of the Study:

• To investigate the splice-dependent roles of FGFR2 isoforms in cancer.
• To highlight the limitations of non-specific FGFR inhibitors.
• To underscore the need for isoform-specific targeting and predictive diagnostics in FGFR-driven cancers.

Main Methods:

• Analysis of peer-reviewed studies on FGFs/FGFRs in cancer.
• Review of RNA splicing mechanisms affecting FGFR2 affinity and function.
• Examination of FGFR2b and FGFR2c isoform activities in relation to tumor suppressor genes (CDH1, PTEN).

Main Results:

• FGFR2b expression promotes apoptotic sensitivity, while FGFR2c drives tumor progression via epithelial-mesenchymal transition.
• FGFR1 and FGFR3 primarily exhibit proliferative actions.
• Splice switching or tumor suppressor gene silencing can convert FGFR2b's tumor-suppressive function to a proliferative one.
• Non-selective pan-FGFR inhibitors may block opposing FGFR2 isoforms, hindering therapeutic efficacy.

Conclusions:

• FGFR2's dual role, dictated by splicing, presents a significant challenge for FGFR-targeted cancer therapy.
• Development of isoform-specific drugs, such as antibodies targeting ligand-FGFR2c binding, is warranted.
• Advanced molecular pathology is needed to predict FGFR2 isoform activity in diverse tumor microenvironments.