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

Abstract

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.

Beyond H&E

“…Canine MCTs with activating mutations in exon 11 respond well to TKIs that are now readily available for dogs. 42,47,61,69,111 Furthermore, high-grade MCTs lacking mutations or aberrant KIT expression have been reported to respond better to a chemotherapy protocol composed of vinblastine and prednisone than to TKI. 140 Similar to the results in dogs, cats with MCTs harboring a mutation in exon 8 have also been reported to have a favorable response to TKIs.…”

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

“…Antitumor efficacy ranges from minimal effects to tumor growth stasis but rarely tumor regression (9,14,15,(18)(19)(20). The variance in response between xenograft models may be attributable to differences in client protein dependence on Hsp90, tumor dependence on the client protein, kinetics of client protein degradation, and resynthesis, as well as, drug pharmacokinetic and pharmacologic properties.…”

Canine Subcutaneous Mast Cell Tumors

“…20,29,38 Mutations result in constitutive activation of KIT, initiating signaling cascades leading to proliferation, survival, and invasion. 9,[15][16][17][18]21,22,29 One group reported that the presence of ITD mutations of c-KIT or aberrant cytoplasmic KIT protein localization was significantly associated with higher values of Ki67. 37 It is not clear from any study of cutaneous MCT if subcutaneous MCT were included; if so, the data could be compromised.…”

“…6,9,11,[14][15][16][17][18][19][20][21][22]29,[36][37][38] Studies show that up to 30% of dogs with MCT have mutations in the juxtamembrane domain, 6,9,20,22,29,37,38 the majority of which are internal tandem duplications (ITD) in exon 11. The presence of these mutations is associated with higher-grade tumors.…”