The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors.
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.


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.
Lin
Tzu-Yin
TY
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Bear
Misty
M
Du
Zhenjian
Z
Foley
Kevin P
KP
Ying
Weiwen
W
Barsoum
James
J
London
Cheryl
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D004283:Dog Diseases / Q000473:pathology; D004285:Dogs; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007946:Leukemia, Mast-Cell / Q000188:drug therapy*; D034801:Mastocytoma / Q000473:pathology / Q000662:veterinary; D051379:Mice; D016513:Mice, SCID; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles; D019009:Proto-Oncogene Proteins c-kit