OBJECTIVE:
Mutations of the
receptor tyrosine kinase Kit occur in several human and canine cancers. While Kit inhibitors have activity in the clinical setting, they possess variable efficacy against particular forms of
mutant Kit and
drug resistance often develops over time. Inhibitors of
heat shock protein 90 (
HSP90), a chaperone for which Kit is a client protein, have demonstrated activity against human cancers and evidence suggests they downregulate several
mutated and imatinib-resistant forms of Kit. The purpose of this study was to evaluate a novel
HSP90 inhibitor, STA-9090, against
wild-type (WT) and
mutant Kit in canine
bone marrow-derived cultured
mast cells (BMCMCs),
malignant mast cell lines, and fresh
malignant mast cells. MATERIALS AND METHODS: BMCMCs,
cell lines, and fresh
malignant mast cells were treated with STA-9090,
17-AAG, and SU11654 and evaluated for loss in cell viability,
cell death, alterations in
HSP90 and Kit expression/signaling, and Kit
mutation. STA-9090 activity was tested in a canine
mastocytoma xenograft model. RESULTS: Treatment of BMCMCs,
cell lines, and fresh
malignant cells with STA-9090 induced
growth inhibition,
apoptosis that was caspase-3/7-dependent, and downregulation of
phospho/total Kit and
Akt, but not
extracellular signal-regulated kinase (ERK) or phosphoinositide-3
kinase (
PI-3K). Loss of Kit
cell-surface expression was also observed. Furthermore, STA-9090 exhibited superior activity to
17-AAG and SU11654, and was effective against
malignant mast cells expressing either WT or
mutant Kit. Lastly, STA-9090 inhibited
tumor growth in a canine
mastocytoma mouse xenograft model. CONCLUSIONS: STA-9090 exhibits broad activity against
mast cells expressing WT or
mutant Kit, suggesting it may be an effective agent in the clinical setting against
mast cell malignancies.
