The
heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client
proteins in
multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown antitumor activities both in vitro and in vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated.
EXPERIMENTAL DESIGN: RESULTS: Our studies revealed that exposure of
KW-2478 to MM cells resulted in growth inhibition and apoptosis, which were associated with degradation of well-known client
proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and
cyclin D1), and FGFR3 was shown to be a new client
protein of Hsp90 chaperon complex. In addition,
KW-2478 depleted the Hsp90 client Cdk9, a transcriptional
kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of
KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and
cyclin D1 expression. In NCI-H929 s.c. inoculated model,
KW-2478 showed a significant suppression of
tumor growth and induced the degradation of client
proteins in
tumors. Furthermore, in a novel orthotopic MM model of i.v. inoculated OPM-2/
green fluorescent protein,
KW-2478 showed a significant reduction of both serum M
protein and MM
tumor burden in the bone marrow.
CONCLUSIONS: