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

Table 1

Key findings from this analysis.

1	The FGFR2 gene undergoes differential splicing in normal epithelial and mesenchymal tissues, resulting in respective FGFR2b and FGFR2c receptor splice isoforms that differ in the affinity of their extracellular domains for specific ligands.
2	The FGFR2b receptor isoform often exerts prodifferentiation and proapoptotic effects, whereas the FGFR2c isoform is promitogenic. Pathological tumor splice switching from FGFR2b to FGFR2b is causally implicated in the mechanism of tumor progression via epithelial-mesenchymal transition (EMT).
3	In the small subset of tumors that overexpress wild-type FGFR2b, heterologous variants of regulatory genes such as CDH1, PTEN, or TP63 are often coexpressed. This implies that interpreting the actionable tumor genotype may require more inclusive consideration of nonactionable genetic aberrations.
4	Small-molecule kinase-inhibitory drugs that simultaneously cross-inhibit FGFR2b and FGFR2c could have unintended and/or conflicting effects in tumor or stromal compartments.
5	Clinically effective tumor-specific FGFR2 drug targeting will depend in part on greater use of nuanced diagnostic assays that clarify which receptor isoform is driving tumor behavior within any unique epistatic context of genetic changes.
6	New FGFR2 isoform-specific drugs are now available for trial use. Their long-term success is likely to be determined in part by the molecular sophistication of patient/cancer selection and by their rational use in combination with other targeted drugs.