Scientific Update: FGFR2 Pathway Activation as a Therapeutic Biomarker for FGFR2 Inhibitors
Fibroblast growth factor receptor 2 (FGFR2) is among cholangiocarcinoma’s most frequently altered genes. Chromosomal fusions and gene rearrangements are particularly common and increase FGFR2 signaling to promote tumor growth. Currently, the FGFR2 inhibitors Pemigatinib (Pemazyre) and Infigratinib (Truseltiq) are FDA-approved for cholangiocarcinoma patients with locally advanced or metastatic tumors harboring FGFR2 fusions/rearrangements that progressed with previous therapy. Accordingly, current clinical indications for treatment with FGFR2 inhibitors focus on detecting FGFR2 alterations in tumor tissue or circulating tumor DNA.
While FGFR2 alterations are central drivers of aberrant FGFR2 signaling in cholangiocarcinoma, a recent study detected increased signaling in some tumors with non-altered FGFR2. The research included 36 cholangiocarcinoma tumors-seven with FGFR2 alterations and 29 with wild-type FGFR2 status. Of the tumors with non-altered FGFR2, 4 (13.8%) showed an increase in FGFR2 downstream signaling indicated by FGF10 (FGFR2 ligand) expression and phosphorylated FGFR2 pathway proteins (pFGFR2/pFRS2α).
These results indicate that FGFR2 signaling can be dysregulated in tumors without FGFR2 alterations, suggesting that FGFR2 inhibitors could benefit a broader subset of cholangiocarcinoma patients. The authors thus propose using clinical biomarkers for FGFR2 pathway activation and FGFR2 alteration detection when considering treatment with FGFR2 inhibitors. While further validation in larger sample sizes is needed, these early results could pave the road for expanded use of FGFR2 inhibitors already in clinical use. Additional studies uncovering the mechanisms of how FGFR2 signaling is dysregulated in FGFR2 wild-type tumors could also inform the development of novel targeted therapies. Such therapies could synergize with existing FGFR2 inhibitors and be part of new combination therapies for FGFR2-dependent tumors.
Reference: Brandi, G., Relli, V., Deserti, M. et al. Activated FGFR2 signaling as a biomarker for selection of intrahepatic cholangiocarcinoma patients candidate to FGFR targeted therapies. Sci Rep 14, 3136 (2024). https://doi.org/10.1038/s41598-024-52991-8
Kelly Butler is an NIH Postbac Research Fellow and the Founding Director of SAFE