Defining the role of HSP90 in the stability of FGFR3 and as a drug target for the treatment of skeletal diseases and cancer

Fibroblast growth factor receptor 3 (FGFR3) regulates growth and differentiation, and its aberrant activation drives skeletal disorders and cancers. This work demonstrates that FGFR3 is inherently unstable and requires Hsp90 chaperone complexes for stability. Using biochemical analyses, we show that Hsp90 inhibition with small molecules (e.g., 17-AAG) induces FGFR3 ubiquitination and degradation. Other chaperone components, including Hsp70, Cdc37, and CHIP, also interact with FGFR3, suggesting additional therapeutic targets. These findings establish Hsp90 as a critical regulator of FGFR3 and support exploring Hsp90 inhibitors in FGFR3-driven cancers, while further studies are needed to assess their potential in skeletal diseases.