Infigratinib is a weak inhibitor of the FGFR3-N540K mutant associated with hypochondroplasia

We read with interest the recent article by Demuynck et al1 on low-dose infigratinib in hypochondroplasia (HCH). The authors’ efforts to develop a therapy for HCH are commendable. However, several important points appear to have been overlooked that need to be considered for accurate interpretation of the scientific evidence and for informing physicians and patients, particularly in the context of the ongoing clinical trials of infigratinib in HCH (NCT06873035; ClinicalTrials.gov). First, Demuynck et al1 failed to acknowledge the extensive evidence suggesting that fibroblast growth factor receptor 3 (FGFR3)-N540K confers poor sensitivity to FGFR3 chemical inhibitors, including infigratinib. In BaF3 cells expressing the TEL-FGFR3 fusion protein, the N540K variant was more than 200-fold less sensitive to inhibition by infigratinib compared with wild-type FGFR3.2 Similarly, in cells expressing the FGFR3-TACC3 fusion oncogene, N540K showed more than 1000-fold greater resistance to infigratinib than wild-type FGFR3.3 In NIH3T3 cells stably expressing different FGFR variants, FGFR1-N546K, FGFR2-N549K, and FGFR4-N535K (homologous to FGFR3-N540K) were more than 1000-fold more resistant to infigratinib than wild-type FGFR1, FGFR2, and FGFR4.4